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x S. Hrg. 103-317 

HUMAN GENOME DIVERSITY PROJECT 



Y 4, G 74/9: S. HRG. 103-317 

Hunan Genone Diversity Project; S.H... 

HEARING 

BEFORE THE 

COMMITTEE ON 
GOVERNMENTAL AFFAIRS 
UNITED STATES SENATE 

ONE HUNDRED THIRD CONGRESS 

FIRST SESSION 



APRIL 26, 1993 



Printed for the use of the Committee on Governmental Affairs 







■ 



**rs 



% 



U.S. GOVERNMENT PRINTING OFFICE 
67-160 cc WASHINGTON : 1993 



For sale by the U.S. Government Printing Office 
Superintendent of Documents, Congressional Sales Office, Washington, DC 20402 
ISBN 0-16-043334-7 






\S 



S. Hrg. 103-317 

HUMAN GENOME DIVERSITY PROJECT 



Y 4. G 74/9: S. HRG, 103-317 

Hunan Genone Diversity Project, S.H. 



HEARING 

BEFORE THE 

COMMITTEE ON 
GOVERNMENTAL AFFAIRS 
UNITED STATES SENATE 

ONE HUNDRED THIRD CONGRESS 

FIRST SESSION 



APRIL 26, 1993 



Printed for the use of the Committee on Governmental Affairs 




■ 



*'rs 






% 



U.S. GOVERNMENT PRINTING OFFICE 
67-460 cc WASHINGTON : 1993 

For sale by the U.S. Government Printing Office 
Superintendent of Documents, Congressional Sales Office. Washington, DC 20402 
ISBN 0-16-043334-7 



. 



COMMITTEE ON GOVERNMENTAL AFFAIRS 
JOHN GLENN, Ohio, Chairman 

SS^? WILLIAM V. ROTH, Jr., Delaware 

CARL LEVIN, Michigan TED STEVENS, Alaska 

^rr S T^^ ER ' Tennessee WILLIAM S. COHEN, Maine 

7^™ RYOR ' Arkan3as THAD COCHRAN, Mississippi 

JOSEPH I. LIEBERMAN, Connecticut JOHN McCAIN, Arizona 
DANIEL K. AKAKA, Hawaii 
BYRON L. DORGAN, North Dakota 

Leonard Weiss, Staff Director 

Shane Merz, Professional Staff 

Franklin G. Polk, Minority Staff Director and Chief Counsel 

Michal Sue Prosser, Chief Clerk 

(II) 



CONTENTS 



Opening statements: Page 

Senator Akaka 1 

WITNESSES 

Monday, April 26, 1993 

Cora Marrett, Ph.D., Assistant Director for Social, Behavioral and Economic 
Research, National Science Foundation 3 

Francis Collins, M.D., Ph.D., Director, National Center for Human Genome 
Research, National Institutes of Health 6 

David J. Galas, Ph.D., Associate Director for Health and Environmental Re- 
search, U.S. Department of Energy 11 

Robyn Nishimi, Ph.D., Senior Associate, Biological and Behavioral Sciences 
Program, Office of Technology Assessment 15 

Luigi Luca Cavalli-Sforza, M.D., Professor Emeritus of Genetics, Department 
of Genetics, School of Medicine, Standord University 25 

Mary-Claire King, Ph.D., Professor of Genetics and Epidemiology, University 
of California at Berkeley 32 

Alphabetical List of Witnesses 

Cavalli-Sforza, Dr. Luigi Luca: 

Testimony 25 

Prepared statement 27 

Collins, Dr. Francis: 

Testimony 6 

Prepared statement 9 

Galas, Dr. David J.: 

Testimony 11 

Prepared statement 12 

King, Dr. Mary-Claire: 

Testimony 32 

Prepared statement 36 

Marrett, Dr. Cora: 

Testimony 3 

Prepared statement 5 

Nishimi, Dr. Robyn: 

Testimony 15 

Prepared statement 17 

APPENDLX 

Letter dated April 30, 1993 to Senator Akaka from Kenneth M. Weiss, Ph.D., 
Professor of Genetics and Anthropology, Head, Department of Anthropol- 
ogy, Pennsylvania State University 43 

Answers to questions from Senator Akaka 44 

Memo with attachments from Professor Henry T. Greely 50 

Letter, with attachments, dated May 5, 1993 to Senator Akaka from Kenneth 
K Kidd, Ph.D., Professor of Genetics, Psychiatry, and Biology, Yale Univer- 
sity 88 



(III) 



HUMAN GENOME DIVERSITY PROJECT 



MONDAY, APRIL 26, 1993 

U.S. Senate, 
Committee on Governmental Affairs, 

Washington, DC. 

The Committee met, pursuant to notice, at 2:11 p.m., in room 
SD-342, Dirksen Senate Office Building, Hon. Daniel K. Akaka, 
presiding. 

Present: Senator Akaka. 

OPENING STATEMENT OF SENATOR AKAKA 

Senator Akaka [presiding]. Aloha and good afternoon. This hear- 
ing of the Governmental Affairs Committee will come to order. 

Today, the Committee will hear testimony on a very ambitious 
project known as the Human Genome Initiative — and a proposed 
supplemental project known as the Human Genome Diversity 
Project. 

The Human Genome project is a worldwide research initiative to 
analyze the structure of human DNA and determine the location 
of the tens of thousands of human genes. The information gen- 
erated by the Human Genome Project will be of immense benefit 
to medical science. 

The Federal commitment to the project is considerable. The 
project is estimated to cost more than $3 billion. Given the planned 
duration and the resources necessary for such an undertaking, a 
project of this magnitude must be dynamic, and research priorities 
must constantly be reviewed. When promising research opportuni- 
ties develop, there must be a mechanism for consideration of sup- 
plemental programs. 

One such supplemental program is the Human Genome Diversity 
Project. Throughout the world, many ethnic and aboriginal groups 
are in danger of losing their genetic identity. There is much that 
we could learn from these diverse cultural groups. The answers to 
many anthropological mysteries are hidden in the genes of these 
ancestral populations. Unfortunately, time is running out. The day 
may soon come when the richness of our genetic diversity is lost 
forever. We may lose the opportunity to learn about ourselves from 
the study of diverse populations. 

The issue to be addressed in this hearing is the potential benefit 
of the Human Genome Diversity Project to medical science. I am 
also sympathetic to cultural and social science investigations that 
increase our understanding of native peoples. 

I welcome the thoughtful comments of our witnesses and hope 
that this hearing will highlight many of the scientifically meaning- 

(l) 



ful accomplishments being made in the study of the human ge- 
nome. 

The hearing record will remain open until the close of business 
May 7, 1993 to provide an opportunity for comments from individ- 
uals and organizations that are not present here today. 

I ask that each witness limit their testimony to 5 minutes to pro- 
vide greater time for discussion. Your written statements will be 
entered into the record in their entirety. 

Prepared Statement of Senator Akaka 

Aloha and good afternoon. This hearing of the Governmental Affairs Committee 
will come to order. 

Today, the committee will hear testimony on an ambitious project known as the 
Human Genome Initiative and a proposed supplemental project known as the 
Human Genome Diversity Project. The Human Genome Project is a worldwide re- 
search initiative to analyze the structure of human DNA and determine the location 
of the tens of thousands of human genes. The information generated by the Human 
Genome Project will be of immense benefit to medical science. 

The Federal commitment to the project is considerable, the project is estimated 
to cost more than $3 billion. Given the planned duration and the resources nec- 
essary for such an undertaking, a project of this magnitude must be dynamic and 
it is important to constantly review research priorities. When promising research 
opportunities develop, there must be a mechanism for consideration of supplemental 
programs. 

One such supplemental program is the Human Genome Diversity Project. 
Throughout the world, many ethnic and aboriginal groups are in danger of losing 
their genetic identity. There is much that we could learn from these diverse cultural 
groups. The answers to many anthropological mysteries are hidden in the genes of 
these ancestral populations. Unfortunately, time is running out. The day may soon 
come when the richness of our genetic diversity is lost forever. We may lose the op- 
portunity to learn about ourselves from the study of diverse populations. 

An important issue to be addressed in this hearing is the potential benefit of the 
Human Genome Diversity Project to the medical sciences. I am also sympathetic to 
cultural and social science investigations that increase our understanding of native 
peoples. 

I welcome the thoughtful comments of our witnesses and hope that this hearing 
will highlight many of the scientifically meaningful accomplishments being made in 
the study of the human genome. 

The hearing record will remain open until the close of business May 7, 1993 to 
provide an opportunity for comments from individuals and organizations that are 
not present today. 

I ask that each witness limit their testimony to 5 minutes to provide greater time 
for discussion. Your written statements will be entered into the record in their en- 
tirety. 

Senator Akaka. I'd like to call our witnesses forward. There will 
be two panels. The first panel will consist of the following — and as 
I call you, will you please come up to the witness table — Dr. Cora 
Marrett, Assistant Director for Social, Behavioral and Economic 
Research, National Science Foundation; Dr. Francis Collins, Na- 
tional Center for Human Genome Research, National Institutes of 
Health; Dr. David J. Galas, Associate Director for Health and Envi- 
ronmental Research, U.S. Department of Energy; and Dr. Robyn 
Nishimi, Biological and Behavioral Sciences Program, Office of 
Technology Assessment. 

I would also like to welcome Dr. Ruth Kirschstein, Director of the 
National Institute of General Medical Science, who is in the audi- 
ence. Aloha and welcome. Dr. Kirschstein has kindly agreed to 
serve as a resource witness. 

At this time, in the order that I called you, please proceed. 

Dr. Marrett? 



TESTIMONY OF DR. CORA MARRETT, ASSISTANT DIRECTOR 
FOR SOCIAL, BEHAVIORAL AND ECONOMIC RESEARCH, NA- 
TIONAL SCD3NCE FOUNDATION 

Dr. MARRETT. Thank you very much, Mr. Chairman. 

I appreciate very much the opportunity to appear before you 
today with my colleagues here at the table and in the audience to 
discuss the Human Genome Diversity Project. 

Recent remarkable advances in molecular genetics have enabled 
the launching of the Human Genome Project, whose mission is the 
decoding of the total package of genetic material, or DNA, in a 
human. This massive effort is well underway and is almost 5 years 
old. It is funded by the National Institutes of Health and the De- 
partment of Energy and currently has an annual budget of approxi- 
mately $180 million. It is still many years away from completion. 

Once the Genome Project produces an entire DNA sequence, we 
will still not have extensive information on the hereditary diversity 
that exists among people — the very large differences that exist 
among people within ethnic groups or populations, and the smaller 
differences that characterize differences among ethnic groups or 
populations. 

The Human Genome Diversity Proposal is a developing effort of 
a group of physical and cultural anthropologists, archaeologists, ge- 
neticists, epidemiologists, and linguists to collect, organize, and 
analyze sufficient DNA from different people and populations to 
answer two major issues. 

The first issue is understanding human genetic change. By lay- 
ing out the specific DNA differences among individuals worldwide, 
it will be possible to reconstruct the relationships and origins of the 
different human populations — the ancient origins of different Na- 
tive American groups, for example, or Polynesians, of different Eu- 
ropean and African groups, and so on. 

The second issue is the hereditary basis for differences in human 
susceptibility to diseases. We are learning weekly the genetic deter- 
mination of many comparatively rare diseases — Huntington's Cho- 
rea, cystic fibrosis, and so on. The list is now thousands long. For 
a very few of these, we know the exact location and DNA sequence 
of the gene involved. 

In addition, we know that the more common diseases, afflicting 
millions of people, often involve both genetic predispositions and 
environmental effects. Well-established cases include breast cancer, 
diabetes, bowel cancer, and at least certain cardiovascular condi- 
tions. These problems and others as well vary in their risk from 
one family to the next and from one ethnic group to the next. He- 
redity clearly plays a role. Learning more about the gene or genes 
that place people at higher risk for these will inevitably help in 
their treatment and prevention. 

I want to stress that the Human Genome Diversity Project is at 
this point still only a proposal. The Human Genome Organization 
and international scientific organizations established a committee 
in 1991 to develop a Human Genome Diversity Project. As a part 
of that effort, the committee in the United States submitted a pro- 
posal to the physical anthropology program at the National Science 
Foundation to support a series of workshops that would develop a 
plan for amassing genetic, linguistic, medical and environmental 



information on a diverse group of human populations from around 
the world. More on the workshops will be filled in by others in this 
panel and the one to follow. 

The physical anthropology program at the National Science 
Foundation coordinated modest levels of funding for these work- 
shops with other programs from the National Science Foundation, 
with the Center for Human Genome Research, the National Insti- 
tute of General Medical Sciences, and the Department of Energy. 

Three of the four planned workshops have now been held. The 
first focused on what an adequate sample of people would be to 
characterize a population. The second focused on what particular 
populations were best candidates for inclusion in the project. Over 
400 populations were identified. The third focused on ethical is- 
sues, biotechnical developments and funding possibilities. The 
fourth will involve international possibilities for collaboration and 
funding. 

Since the project clearly must be an international one, there has 
been an attempt from the outset to enlist cooperation and parallel 
funding from other countries. European members of the Human 
Genome Organization Committee have worked to establish funding 
to support the Human Genome Diversity Project and are working 
to allow funding for European components of the project. They have 
secured some funding to begin work, and we can say more about 
the international funding, again, at a later point. 

The structure of the project that is evolving will have at its cen- 
ter an international Human Genome Diversity Scientific Commit- 
tee. A second committee of importance will be the Ethics Commit- 
tee, a committee to monitor, assess and anticipate the complex eth- 
ical issues that inevitably will develop. 

The project then can be thought of as divided into three parts. 
The first is the collection phase, involving the identification of ap- 
propriate populations or groups to be covered in the survey; the col- 
lection of required family, medical, demographic, cultural and eco- 
logical information, and the taking of blood samples from cooperat- 
ing individuals. At this point, at least 400 groups worldwide are 
likely to be included. 

The second part involves the transformation and storage of the 
blood samples themselves in central laboratories. Along with the 
other data collected on the populations, stored in computer files, 
these will make a permanent and inexhaustible source of informa- 
tion for future scientific and health research. 

The third part is the analysis phase, which will extend for some 
time into the future. 

As we see it, this is an idea whose time has come. You mentioned 
earlier the rapidity with which diversity is disappearing, being 
eroded and obscured by a variety of forces as there is the penetra- 
tion of heretofore isolated ecologies and environments, and chang- 
ing diets and lifestyles accompanying the alterations that take 
place. 

We need a systematic collection of information, genetic and oth- 
erwise, on the diversity of human populations before they become 
even more diluted by the growing global mobility of peoples. This 
will be an invaluable resource for understanding our origins and 



our hereditary accommodations and susceptibilities to the diseases 

that afflict us. 

Thank you, Mr. Chairman. I'd be pleased to answer questions at 
the time you'd like to raise them. 

Senator Akaka. Thank you very much, Dr. Marrett. 

Prepared Statement of Dr. Cora Marrett 

Mr. Chairman and Members of the Committee, I appreciate very much the oppor- 
tunity to appear before you today with my colleagues from the National Institutes 
of Health, the Energy Department, and the Office of Technology Assessment to dis- 
cuss the Human Genome Diversity Project. 

RELATION TO THE HUMAN GENOME PROJECT 

Recent remarkable advances in molecular genetics have enabled the launching of 
the Human Genome Project, whose mission was the decoding of the total package 
of genetic material, or DNA, in a human. This massive effort is well underway and 
is almost five years old. It is funded by the National Institutes of Health and the 
Department of Energy, and currently has an annual budget of approximately $180 
million. It is still many years away from completion. 

Once the Genome Project produces an entire DNA sequence, we will still not have 
extensive information on the hereditary diversity that exists among people— the 
very large differences that exist among people within ethnic groups or populations, 
and the smaller differences that characterize differences among ethnic groups or 
populations. 

The Human Genome Diversity Proposal is a developing effort of a group of phys- 
ical and cultural anthropologists, archaeologists, geneticists, epidemiologists, and 
linguists to collect, organize, and analyze sufficient DNA from different people and 
populations around the world to answer two major issues. 

OBJECTIVES OF THE HUMAN GENOME DIVERSITY PROJECT 

The first issue is understanding human genetic change. By laying out the specific 
DNA differences among individuals world-wide, it will be possible to reconstruct the 
relationships and origins of the different human populations — the ancient origins of 
different Native American groups, for example, of Polynesians, of different European 
and African groups, and so forth. 

The second issue is the hereditary basis for differences in human susceptibility 
to diseases. We are learning weekly the genetic determination of a many compara- 
tively rare diseases — Huntington's Chorea, cystic fibrosis, and so on. The list is now 
thousands long. For a very few of these, we know the exact location and DNA se- 
quence of the gene involved. 

In addition, we know that the more common diseases, afflicting millions of people, 
often involve both genetic predispositions and environmental effects — well-estab- 
lished cases include breast cancer, diabetes, bowel cancer, and at least certain car- 
diovascular conditions. These problems, and others as well, vary in their risk from 
one family to the next and one ethnic group to the next. Heredity clearly plays a 
role. Learning more about the gene or genes that place people at higher risk for 
these will inevitably help in their treatment and prevention. 

CURRENT STATUS OF THE HUMAN GENOME DIVERSITY PROPOSAL 

I want to stress that The Human Genome Diversity Project is, at this point, still 
only a proposal. The Human Genome Organization (HUGO), and international sci- 
entific organizations, established a committee in 1991 to develop a Human Genome 
Diversity Project. As part of that effort, the committee members in the United 
States, including Dr. Cavalli-Sforza and Dr. King, submitted a proposal to the Phys- 
ical Anthropology Program at NSF to support a series of workshops that would de- 
velop a plan for amassing genetic, linguistic, medical, and environmental informa- 
tion on a diverse group of human populations from around the world. A NSF Phys- 
ical Anthropology Program coordinated modest levels of funding for these workshops 
with selected other NSF programs, with the Center for Human Genome Research, 
the National Institute of General Medical Sciences, and the Department of Energy. 

Three of four planned workshops have now been held. The first focused on what 
an adequate sample of people would be to characterize a population. The second fo- 
cussed on what particular populations were best candidates for inclusion in the 
project. Over 400 populations were identified. The third focussed on issues, 



biotechnical developments, and funding possibilities. The fourth will involve inter- 
national possibilities for collaboration and funding. 

Since the project clearly must be an international one, there has been an attempt 
from the outset to enlist cooperation and parallel funding from other countries. Eu- 
ropean members of the HUGO committee have worked to establish funding to sup- 
port the HGD project, and are working to allow funding for European components 
of the HGD project They have already secured some funding to begin work. Tech- 
nical and scientific representatives of the E.C. and Japan have also been invited to 
the workshops, and individual scientists from a number of countries around the 
world have participated in the workshops. Certain private agencies likely to be in- 
terested in the project have also been approached by the organizers. 

The structure of the project that is evolving will have, at its center, an Inter- 
national HGD Scientific Committee. A second committee of importance will be the 
HGD Ethics Committee, to monitor, assess and anticipate the complex ethical issues 
that will inevitably develop. 

The project itself can be thought of as being divided into three parts. 

The first part will be the collection phase. This involves the identification of ap- 
propriate populations or groups to be covered in the survey; the collection of re- 
quired family, medical, demographic, cultural and ecological information (on each 
group if it has not already been made); and the taking of blood samples from cooper- 
ating individuals. At this point, at least 400 groups world-wide are likely to be in- 
cluded. 

The second part involves the transformation and storage of the blood samples 
themselves in central laboratories. Along with the other data collected on the popu- 
lations, stored in computer files, these will make a permanent and inexhaustible 
source of information for future scientific and health research. 

The third part is the analysis phase, which will extend for some time into the fu- 
ture. 

SUMMARY 

This is an idea whose time has come. The great hereditary diversity of humanity 
is rapidly being eroded or obscured by the same forces that are transforming so 
much of our world today — increased ease of movement and migration, the penetra- 
tion of heretofore isolated ecologies and environments by the world economy and its 
representatives, and changing diets and life styles accompanying these alterations. 
We need a systematic collection of information, genetic and otherwise, on the diver- 
sity of human populations before they become even more diluted by the growing 
global mobility of peoples. This will be an invaluable resource for understanding our 
origins and our hereditary accommodations and susceptibilities to the diseases that 
afflict us. 

Senator Akaka. Dr. Francis Collins, we'd be pleased to have your 
testimony. 

TESTIMONY OF DR. FRANCIS COLLINS, DIRECTOR, NATIONAL 
CENTER FOR HUMAN GENOME RESEARCH, NATIONAL INSTI- 
TUTES OF HEALTH 

Dr. Collins. Thank you, Mr. Chairman. 

I am happy to address this issue in my first appearance before 
a congressional committee since becoming Director of the National 
Center for Human Genome Research on April 4th. 

I am a physician and a geneticist. I have been involved, prior to 
taking on this position, in the search for genes that cause human 
disease, particularly cystic fibrosis, neurofibromatosis, Huntington's 
disease, and breast cancer. I am fascinated by the opportunities 
that genetic research presents for a better understanding of our- 
selves, for improving our health, and for reducing health care costs. 

I want to distinguish between the Human Genome Project (which 
is now underway, supported by a combination of sources including 
the NIH and the Department of Energy) and the Diversity Project, 
which is the topic of today's discussion. As Dr. Marrett has said, 
the Diversity Project is a proposal seeking a direction. 



The Human Genome Project, I believe, is the most important, ex- 
citing, and potentially beneficial scientific effort that humankind 
has ever undertaken. I know that sounds like a very strong state- 
ment, but I think it is quite defensible. 

The map and the sequence of all 100,000 human genes, which we 
expect to have by the year 2005, will tell us the basis of the 4,000 
or so genetic diseases which afflict us. They will also tell us about 
the genetic basis of more common disorders like diabetes and hy- 
pertension. Almost no one has a family history that is completely 
without examples of familial illnesses. 

This genetic information will lead us to much better diagnostics 
and to treatments that we haven't dreamed of before. For cystic fi- 
brosis, for example, the finding of the gene 3 years ago has led to 
the initiation of gene therapy trials within the past 2 weeks. This 
is a very telescoped time period, and such examples will be seen 
again as we discover other genes for genetic disease. 

Huntington's disease has already been mentioned. After a long 
search, that gene has emerged within the last month. The rate of 
acceleration of genetic disease gene identification is really quite 
dramatic. 

One of the beauties of the Human Genome Project is that it is 
already producing these kinds of results early on in its progress; 
you don't have to wait until the end to enjoy the benefits. 

A gene for breast cancer is being avidly sought in a collaboration 
between my research group and that of Dr. Mary Claire King, one 
of the later witnesses, as well as a number of other groups around 
the world. That gene on Chromosome 17, is carried by one in 200 
women and if you have it, places you at a very high risk of breast 
cancer. That gene will probably be found within the next year. The 
identification of that gene and the ability to identify women who 
are at very high risk and get them into intense surveillance pro- 
grams promises to do much for this terrible disorder that strikes 
so many. In itself this finding may be able to actually pay back the 
costs of the Genome Project which are, I would argue, rather mod- 
est for the benefits that the project will produce. 

I think it is useful to make a quick comment on the history of 
the Human Genome Project as we now look at the Diversity Project 
and try to plan the best way to move forward. Let me say at the 
outset that I support the Diversity Project. I think it is useful, how- 
ever, to consider the best way to get a very complicated scientific 
endeavor of this sort, with many ethical dimensions, underway. 

For the Human Genome Project, discussions about carrying out 
this activity began in about 1985. In a series of scientific meetings, 
ideas about how the project might be organized were put forward. 
The project's goals modulated considerably during those 2 or 3 
years. In my view, a very important part of that process was an 
external review of the Genome Project by the National Research 
Council and another one by the OTA, represented here today. That 
provided an opportunity for those who were not themselves in the 
middle of the effort to stand back and look at the goals, to think 
carefully about the budget, and to make suggestions as to the best 
organizational structure to get the job done. 

Those reports were carefully reviewed, and when the Genome 
Project's organization was set up, it was done with detailed goals 



8 

and timetables. We have adhered to these very tightly since that 
time. The Genome Project is thus a very focused effort. It is focused 
on developing genetic and physical maps, and the sequences of the 
human genome, as well as that of model organisms that tell us 
more information about the human genome. 

Partly as a result of the advice received in those early stages, a 
strong component of the Human Genome Project is the Ethical, 
Legal and Social Implications (ELSI) Branch. This Branch has 
been devoting much attention to the consequences of having in- 
creased ability to obtain genetic information on individuals in the 
population and particularly how to avoid the chance that people 
will be discriminated against on the basis of genetic information 
that is determined about them. Five percent of the genome budget 
is now devoted to this ELSI program, and most observers think it 
is a very crucial part of the whole endeavor. 

The Genome Project is going extremely well. The goals that we 
set for ourselves in genetic and physical mapping are actually 
being exceeded despite the fact that the budget for this effort has 
never achieved the full ramp up that was suggested by the original 
review panels. 

So we are running lean, but determined to succeed, and we really 
have a lot on our plate to get this job done. 

I support the Diversity Project as a fascinating scientific endeav- 
or, with great consequences for our understanding of the related- 
ness and origins of human populations. I believe that we will learn 
things about medical disorders as well, although those con- 
sequences are a little less easy to be certain of at the present time 
and will require further study. The present plan calls for collecting 
blood samples from about 25 members of each of 400 populations. 
Unless a particular disease gene is rather frequent in a particular 
population, there is a good chance it would not be seen in such a 
small number of blood samples. But obviously this is a trade-off be- 
tween cost and benefit. 

I am concerned, however, about the social implications of this 
project, and I'm sure that will be discussed this afternoon. Will the 
Third World, in which many of these populations currently reside, 
feel exploited by the project's coming in and obtaining samples 
from such individuals? I think it is crucial to obtain consultation 
at an early stage from representatives of that community to antici- 
pate the lands of reactions which will come about. 

How will we handle informed consent in situations where the 
usual U.S. Government rules may be difficult to put into place as 
regards the written aspects of informed consent? Perhaps most im- 
portantly, how will we guard against misuse of this information? 
By determining information about ethnic groups that characterizes 
them and differentiates them from each other, there will be the 
possibility of demagogues taking that information and using it to 
discriminate against ethnic groups. I believe that we can protect 
against that outcome if we prepare carefully for it, but I think a 
great deal of attention needs to be paid to that issue before we get 
too far along. 

For those reasons, I believe that the experience gained through 
setting up the Human Genome Project applies to the Diversity 
Project, and that it would be very appropriate at this juncture to 



9 

have a review, perhaps by a body like the NRC, of this project, to 
make specific recommendations about goals, budgets, and how to 
handle the very thorny ethical issues. 

I appreciate the chance to offer these comments, and I would be 
happy to answer questions. 

Senator Akaka. Thank you very much, Dr. Collins. 

Prepared Statement of Dr. Francis Collins 

Mr. Chairman, Senator Akaka, and Members of the Committee, it is my pleasure 
to appear before you today as the new Director of the National Center for Human 
Genome Research (NCHGR) of the National Institutes of Health (NIH) and to have 
the opportunity to talk to you about the Human Genome Project. I am enormously 
pleased to be at the helm of what I consider to be the single most important sci- 
entific endeavor we have ever embarked upon. By the end of the 15-year project, 
we hope to have produced detailed maps of all the human chromosomes and deter- 
mined the sequence of the 3 billion pairs of nucleotide bases that make up human 
DNA. This information will be stored in databases that will allow researchers to 
have access to any region of the human genome right at their fingertips. The mul- 
titude of benefits we are witnessing already from the Human Genome Project is only 
the beginning of what I believe will be a revolution in molecular medicine and 
human biology. 

Goals of the Human Genome Project 

The Human Genome Project is an international research effort that has the goal 
of analyzing the structure of human DNA and determining the location of the esti- 
mated 100,000 genes located on 23 pairs of humeri chromosomes. In the United 
States, the Human Genome Project is managed principally by two government agen- 
cies, the NIH and the Department of Energy (DOE), who together have set specific 
scientific goals in an initial 5-year plan to manage this historic effort. You will also 
be hearing testimony today from Dr. David Galas of the DOE. 

The primary mission of the Human Genome Project is to develop research tools — 
chromosome maps, DNA sequence information, laboratory technology, and computer 
databases — that will allow researchers to find and analyze genes faster, more easily, 
and more cheaply. These tools will have tremendous benefits for biomedical research 
and make important contributions to a variety of research projects. Of primary in- 
terest are the extraordinary medical benefits that will result from our ability to un- 
derstand the genetic factors of health and disease. Gene discovery gives researchers 
the opportunity to study the function of the gene and its role in cell biology. This 
knowledge will revolutionize our strategies to diagnose, treat, and even prevent 
many diseases. 

Medical Benefits 

The pace of disease gene discovery has increased substantially because of the re- 
search tools developed by the Human Genome Project. We have seen the discovery 
of genes responsible for genetic diseases such as cystic fibrosis, neurofibromatosis 
type I and II, fragile X, and most recently, you may have heard about the discovery 
of the gene responsible for Huntington's disease. In collaboration with another of to- 
day's witnesses, Dr. Mary-Claire King, my colleagues and I are also zeroing in on 
a gene that causes breast cancer — I expect that the gene will be located within the 
next year. It is a gene that 1 out of 200 women inherit; these women have an 85 
percent chance of getting breast cancer and have an increased risk of ovarian cancer 
as well. We hope soon to be able to offer diagnostic testing for women at risk, and 
eventually develop ways to treat and prevent this type of early-onset breast cancer. 

The isolation of the cystic fibrosis gene provides a good example of the progress 
that can be made in understanding a disease once the gene is isolated. I was part 
of a team of researchers who isolated the gene in 1989, and I am excited to report 
that we have already begun to design new, highly specific drugs to treat cystic fibro- 
sis and are in the process of developing gene therapy techniques. The first human 
gene therapy experiment targeting cystic fibrosis began this month on the NIH cam- 
pus by researchers at the National Heart, Lung and Blood Institute. The ability to 
begin gene therapy trials less than 4 years after the gene was discovered is a dra- 
matic example of the power of the new tools of human molecular genetics. NIH has 
recently established a Division of Intramural Research within the NCHGR which 
will focus on technologies for finding disease genes and developing subsequent DNA 
diagnostics and gene therapies. 



10 

The Human Genome Project is cutting edge basic science, and is providing the re- 
search tools to accelerate our understanding of the biological and molecular proc- 
esses that permit human life to develop and function. This will profoundly affect our 
ability to understand the molecular basis of disease and will greatly improve our 
ability to diagnose, treat, and prevent many common diseases resulting from mal- 
functions or mutations in our genes. Such diseases represent a major fraction of the 
chronic conditions that account for most of the health care costs today. 

The Human Genome Diversity Project 

The Human Genome Diversity Project, which we are here to discuss today, is one 
of the many research projects that will be greatly benefitted by the genome analysis 
tools being developed hy the Human Genome Project. The objectives of the Human 
Genome Diversity Project are to collect, analyze, and preserve genetic samples from 
a host of vanishing human populations. This project has the potential of giving us 
new knowledge about human origins, evolutionary history, and genetic diversity; it 
may also eventually lead to a better understanding of the frequency and suscepti- 
bility to disease among diverse populations. It is timely to discuss the undertaking 
of the Human Genome Diversity Project; I am mindful that researchers wish to col- 
lect the samples now before we lose the opportunity due to the further breakdown 
of geographical barriers, war, famine, or disease. 

The Human Genome Diversity Project is beyond the mission of the federally fund- 
ed Human Genome Project. The NIH and DOE are facing challenges to accomplish 
the goals we set out to achieve within the next 15 years. We have a long road ahead 
to complete the genetic and physical maps of all the human chromosomes, and it 
is essential that there be further improvements in sequencing technology if we wish 
to sequence the entire human genome quickly and efficiently. We have been able 
to make significant progress because we have clearly defined our mission. At this 
time, the Human Genome Project's major contribution to the Human Genome Diver- 
sity Project would be for us to continue to develop the research tools that will allow 
genetic diversity research, as well as other scientific research disciplines, to proceed 
in a cost-effective way. There may be aspects of technology development, for exam- 

gle high throughput genotyping of many DNA samples, which will benefit both the 
[uman Genome Project and genetic diversity studies, and we look forward to ex- 
ploring those complementary areas. 

I believe the Human Genome Diversity Project is a valuable international endeav- 
or, and that the NIH should cooperate in this project. We are pleased that the 
NCHGR was able to participate in and contribute funding to the National Science 
Foundation's grant to the Human Genome Organization (HUGO) Conmittee for 
Human Genetic Diversity for a series of workshops on the Human Genome Diversity 
Project. The National Institute of General Medical Sciences at NIH and the DOE 
were also contributors. The most recent workshop took place on February 16-18, 
1993, on the NIH campus in Bethesda, Maryland, and it included discussions on the 
ethical issues surrounding genetic diversity research. 

Ethical, Legal, and Social Issues 

The information generated by the Human Genome Diversity Project will further 
our knowledge about our human origins and evolution, but it also will raise some 
challenging ethical, legal, and social issues that must be identified and addressed 
before the project begins. The February workshop raised several of these important 
issues including: (1) the ethical issues raised in doing biomedical research in devel- 
oping countries and insuring the protection of human subjects (for example, it is dif- 
ficult to ascertain what "informed consent" means in other cultures to know if an 
individual is voluntarily participating in the sample collection process); (2) the lega' 
issues raised by the possible commercial value of the project's samples or results; 
and (3) the social-political issues surrounding the possible misuse or misinterpreta- 
tion of the information generated. Research concerning human genetic differences 
always merits careful attention to avoid notions of superiority or inferiority among 
diverse populations. 

The Human Genome Project has also faced challenging issues related to the use 
of human genetic information. At the NCHGR, the Ethical, Legal, and Social Impli- 
cations Branch was created to define these issues and to develop initial policy op- 
tions to address them. Five percent of our budget is devoted to the activities of this 
branch. Our experience has shown that the need is great to examine the ethical, 
legal, and social issues — alongside with the scientific research — in order to minimize 
any adverse social consequences resulting from the generation of genetic informa- 
tion. 

I would recommend that the Human Genome Diversity Project, as it is organized 
and funded, develop mechanisms to address the ethical and legal challenges the 
project will encounter. I would further suggest that an advisory group be established 



11 

to monitor the research and the use of the information it generates. My staff and 
I would be happy to provide consultation and advice based on our own experience 
in this endeavor. 
I would be pleased to answer any questions that you may have. 

Senator Akaka. Dr. Galas? 

TESTIMONY OF DR. DAVID J. GALAS, ASSOCIATE DIRECTOR 
FOR HEALTH AND ENVIRONMENTAL RESEARCH, U.S. DE- 
PARTMENT OF ENERGY 

Dr. Galas. Thank you, Mr. Chairman. 

I am honored and pleased to be here with you today to discuss 
the Human Genome Project and the issue on the table. My col- 
leagues have been rather eloquent, particularly Francis in his de- 
scription of the Genome Project, and I can probably be a bit briefer 
as a result. 

The scientific questions that are concerned with the genetic di- 
versity of humankind are indeed extremely important questions — 
there is no question about that — and all the more fascinating be- 
cause they really deal with who we are and where we came from. 
So as to the issues at hand, I don't think anyone would disagree 
with the statement that these are extremely important and very in- 
teresting questions that lie before us in the unknown area of sci- 
entific investigation. 

Now, the important issue for us here is the relationship of this 
proposed effort to explore genome diversity to the Human Genome 
Project. I am delighted that I can report to you in much the same 
tone that Francis began that the Human Genome Project is now 
going extremely well. Progress is outstanding, and the cooperation 
between the National Institutes of Health and the Department of 
Energy is increasing, and I have every confidence that in spite of 
the fact that the budgetary projections which lead to the number 
of $3 billion have not been met, we are still doing extremely well 
both in the areas of technology development as well as in the area 
of actually beginning to develop maps and doing things that per- 
haps a couple of years ago, when we began planning this, we would 
not have thought we would be able to do. 

But we have a long way to go; there is no question about that. 
We are well-launched on this journey, but it is only beginning. 

So to the relationship between the Human Genome Diversity 
Proposal and the Human Genome Project, it is clear that there are 
many potential relationships, but I think the key things are that 
the Human Genome Project will be able to provide technology and 
scientific information and be a scientific resource for much of fu- 
ture biology and medicine. In fact, it is just in those terms that the 
project was framed, and indeed, all of the thinking that went into 
that has been borne out in my view that the potential for the sci- 
entific basis of biology in the 21st century and in the practice of 
medicine, the development of medical technology, is an extraor- 
dinary benefit of the Human Genome Project as it stands. The de- 
velopment of the Human Genome Project as a scientific resources, 
I think, is a very important concept here. 

So the medical implications of the Human Genome Project, doing 
all of medical genetics, medical technology development, must be 
viewed as being very important spinoffs or important supplemental 



12 

projects that already exist to the Human Genome Project because 
it is indeed the foundation of much of future biology and medicine. 

The other comment I would like to make is that I, too, am very 
concerned about the potential ethical, legal and social issues that 
are raised by the proposals for the Human Genome Diversity 
Project, and I don't think anyone would slight the importance of 
those. Those are things that have to be looked at extremely care- 
fully. Misuse of genetic information is something that we have not 
dealt with well yet in this country from a legal and policy point of 
view, and the project, the NIH/DOE Human Genome Project, has 
been looking very carefully at these issues, and I think at least 
some of the benefits of those studies and the concerns that have 
been raised as a result should go into a very careful planning proc- 
ess to doing something like a Human Genome Diversity Project. 

The final comment I would have is that I think this project, 
much like Francis said, must stand on its merits, scientifically, in- 
sofar as its goals are concerned, whether they be anthropological, 
linguistic, medical or whatever; it must be reviewed extremely 
carefully, and if that is done, and if it is planned in such a way 
that it maximizes the benefit to mankind both from the point of 
view of scientific information and from the potential medical bene- 
fits — and this is reviewed very carefully on a sound scientific 
basis — I am sure that the Human Genome Project can provide a 
great deal of the technological knowledge and scientific information 
that could make it a success. 

Thank you very much. I'd be happy to answer questions. 

Senator Akaka. Thank you, Dr. Galas. 

Prepared Statement of Dr. David J. Galas 

I am very pleased to have the opportunity to discuss the historic Human Genome 
Project with you today. In many ways, the Human Genome Project epitomizes the 
promise of the biological sciences for the future. The impact on our lives of the vast 
amount of new knowledge of the living world is just beginning to be realized— it will 
inevitably transform the biological sciences, medicine, as well as agriculture, food 
manufacture, chemical technology, and many other areas in ways that are difficult 
to predict. The project is even now producing a strong shift in the biomedical 
sciences, from descriptive phenomenology to fundamental understanding, and 
changes in the practice of medicine will not be far behind. One of the most signifi- 
cant of these latter changes will be a shift in emphasis from curative to preventative 
medicine — from therapy to prevention. This shift will soon begin to occur because 
the research that focuses on the fundamental genetic determinants of the function- 
ing of the human body will enable more and more detailed understanding of the na- 
ture and causes of human diseases. This will, in turn, allow effective prevention, 
early intervention and more benign and less costly treatment. This knowledge will 
include an understanding of the propensities of different individuals for different 
diseases -and susceptibilities to health-endangering practices and environmental in- 

fluGIlCGS 

The Department of Energy (DOE) has sponsored the Human Genome Project 
(HGP) from its inception. At that time, it was recognized that the essential tech- 
nology which would enable us to undertake this historic project was within our 
reach, and that immense potential benefits to biology and medicine could be real- 
ized. The DOE and the National Institutes of Health (NIH) jointly support this na- 
tional research effort, carefully coordinating our respective programs. 

The HGP is a project that also holds within its promise some significant issues 
and questions concerning the nature and uses of human genetic information. While 
the promise of human genome research is enormous, some of the ethical, legal, and 
social issues associated with this new knowledge are serious and difficult. The HGP 
has supported an unprecedented effort — more than 3 percent of its budget is devoted 
to the effort— to study these issues and examine the ethical, legal and social con- 
sequences of the coming deluge of genetic information and the new, associated tech- 



13 

nologies. These issues include the proper legal restraints on discrimination based on 
genetic information and the rights to privacy of genetic information and their con- 
sequences. It has been well recognized that ethical, legal, and social impacts will 
accompany greater knowledge about the human genome and that some attempts 
need to be made to anticipate, and to try to ameliorate, these impacts. Another issue 
has to do with the proper distribution for the public good of intellectual property 
rights for genetic material and information — patents on genes. 

We consider this historic project to be of immense potential value to the American 
people and to the world. Thus, we strongly support the expeditious transfer of the 
benefits of this research and of the associated technologies to the public, which of 
necessity involves the patent system. This issue has been discussed elsewhere, and 
I will not comment further here on the gene patenting issue. 
Goals and Progress of the Human Genome Project 

The general approach to elucidating the genetic contents of the genome is to phys- 
ically ,{ map" the chromosomes and then sequence large parts of it. Mapping one of 
the 24 distinct human chromosomes means producing a linear series of DNA frag- 
ments, containing genes, that extend collectively from one end of that chromosome 
to the other. This would then enable the location, isolation and characterization of 
all of the individual genes and functional sites in that chromosome. The over-arch- 
ing goal of the HGP is to create a knowledge base of unprecedented detail and com- 
plexity as a resource for scientific investigations that will enable subsequent re- 
search to be immensely more effective and efficient. The process of mapping chro- 
mosomes is well underway and, it is fair to say, is making spectacular progress. 
Never before has so much genetic information been gained, and so many genes lo- 
cated, identified or characterized so rapidly. Never before has the technical means 
to gain information been more promising. Never before has so much biological 
knowledge been generated as during the past few years of genome research. No 
matter how strongly I emphasize it, you will undoubtedly be surprised in the next 
few years by the sheer rate at which new information is produced. Let me cite a 
few recent examples to illustrate this point. Hardly a week goes by now that a dis- 
covery in human genetics, relevant to some heritable disease, does not appear in the 
gopular press. Recently, genes involved in muscular dystrophy, fragile-X syndrome, 
[untington's disease, "Lou Gehrig's disease" and many others have been discovered 
because of advances in human genetic knowledge. These discoveries are the harbin- 
gers of much more new knowledge that will be gained because of the HGP. The re- 
source of knowledge of genomic maps, for example, now allows disease-related genes 
to be found much more efficiently. This prospect of new knowledge offers great 
promise and opportunity to many different branches and disciplines of the biological 
and medical sciences. 

The original and explicit intent for the Human Genome Project (as arrived at by 
the DOE Office of Energy Research and the NIH National Center for Human Ge- 
nome Research, and defined in the 1988 DOE-NIH Memorandum of Understanding 
and the interagency 5-year plan which commenced on October 1, 1990), is clear. 
Broadly speaking, the goals are twofold and include the mapping and sequencing 
of the entire human genome, along with the development of advanced technologies 
and instrumentation to achieve these ends. They also include the development of 
the informatics capabilities to manage, access, and analyze the resulting data. It is 
the aim of the U.S. Human Genome Project to accelerate future biological science 
by building the tools, material resources, and infrastructure so that other branches 
of science, to be determined by the aggressiveness and imagination of their practi- 
tioners, can make the greatest use of these new methods and tools. In other words, 
the HGP is directed at building a scientific resource of unprecedented complexity 
and power. Many scientific research enterprises will make use of this resource: med- 
ical genetics, for the diagnosis and treatment of disease; and fundamental biology, 
for the detailed understanding of biological function, to give two examples. Surely, 
population genetics and anthropology will also be among the early exploiters of the 
new genetics made possible by the HGP. 

Human Genetic Diversity 

Let me turn now to the specific emphasis of the present hearing — the question 
of the nature of human genetic diversity and the research intended to elucidate it. 
The fundamental scientific questions concerning the nature and full extent of 
human genetic diversity are very important. The origins and histories of human 
populations, and the extent to which the genome can and does vary among the 
present human population, are momentous and fascinating scientific issues. The 
area of human molecular population genetics has recently attracted much attention, 
and the opportunities facilitated by new methods, technologies and approaches 
made possible by advances in molecular biology and genetics are indeed exciting 



14 

prospects. It is now possible to distinguish the relatively distant genetic origins of 
individuals, in addition to being able to distinguish individuals from one other. The 
former is based on differences in the human genome that persist throughout large 
groups of people with common heritage. The latter is sometimes referred to as DNA 
forensics, and is based on relatively recent genetic changes that result in differences 
among individuals. It is important to recognize, however, the natural boundary be- 
tween the building of a powerful scientific resource, which is the HGP, and a broad 
field of scientific investigation that encompasses physical anthropology, human evo- 
lution and population genetics. 

For several reasons, it would be a serious mistake to ignore this distinction and 
attempt to bring this sort of research initiative under the umbrella of the HGP. The 
importance and breadth of the questions of human genetic diversity are such that 
this research should be constituted as an effort that is clearly distinct from the 
HGP, both in organization and funding. The most direct reason is that the goals of 
the research are clearly distinct and, in some ways, derivative of the genome project. 
The HGP can provide an invaluable resource for planning, designing and launching 
a research program focused on human diversity, but such a program would clearly 
not fit the central goals of the HGP. To divert any part of the HGP to address these 
issues now would be a great disservice to other areas of biology and medicine that 
are likewise dependent on the acquisition of the knowledge resources being derived 
from the genome project, and which could make similar claims to scarce sources of 
support. In addition, it must be noted that the more focused and timely the acquisi- 
tion of the HGP data is, the more effective a human genetic diversity project will 
be. Thus, any diversion from the goals of the HGP would, in the long view, detract 
from diversity studies as well as others. 

There are, then, substantive reasons for keeping diversity studies distinct from 
the HGP. Let me now turn for a moment to some considerations on the planning 
for such a project. First, I will discuss an issue that is distinct from the scientific 
questions. Before starting an initiative like this one, serious thought must be given 
to the impact on the population to be studied, especially in the area of ethical, legal, 
and social implications of the research itself and the information it could produce. 
These are serious issues. Privacy, discrimination and legal and social issues in the 
research locales are significant considerations in planning such a project, and must 
not be slighted. Of course, since all federal agencies have subscribed to a 'Tederal 
Policy for the Protection of Human Subjects" (10 CFR Part 745)— and part of this 
rule is that all human subjects, anywhere in the world, must be treated as they 
would be in this country — all subjects and all information deriving from this re- 
search would have to be treated with the great care specified in those rules. In addi- 
tion, Third World countries may not feel that providing unlimited access to their 
"genetic resources" without assurances of various kinds, perhaps including com- 
pensation, is in their best interests. Also, how other research workers, unconnected 
with the immediate research but having access to the data, might make use of bio- 
logical materials and information created by this project is a serious issue and must 
be considered. These difficult issues have not received much attention to date. It is 
clear to me that it would be irresponsible not to have these issues clearly addressed 
before such research ensues. 

I have argued that the human diversity research should not be considered to be 
a part of the HGP. I have also pointed out that there are several societal obstacles 
that must be overcome to carry out such research in an effective and responsible 
manner. I would like to mention now that there are significant scientific issues that 
need to be considered further before this research project should be considered for 
significant support. 

While the differences between two human genomes can be significant in what 
they could tell us about their respective genetic origins, the differences between two 
human genomes appear to be, at any one position, of the order of one part in one 
thousand. There are regions that are highly variable, changing rapidly so that only 
close relatives share the same sequence — the basis for DNA forensics. There are also 
much more slowly varying regions that are shared by most individuals with rel- 
atively distant genetic heritage. What this means is that very careful considerations 
must go into devising a plan for sampling a human population before it is likely 
to be useful. The genetic differences being looked for must be anticipated to some 
extent in order to plan the sampling properly. If one is searching for characteristic 
genetic differences that can mark historical and recent ore-historical populations, 
one must be very careful to understand the genetic markers one is studying, and 
tailor the sampling scheme to the genetics. It has also been suggested that very im- 
portant information about medical genetics is to be gained oy sampling diverse 
human populations. While this is certainly true in principle, it is also clear that this 
kind of information is unlikely to derive from a program that takes a few samples 



15 

from a widely diverse set of groups and individuals. The point of this discussion is 
simply that a great deal remains to be done to arrive at a robust plan for such a 
program if it is likely to be useful to science and to humanity. 

Because of our interest in fostering the productive use of genome research in re- 
lated areas, the DOE, as well as the NIH and the National Science Foundation, 
have provided some support to interested scientists to hold several planning meet- 
ings over the course of the past year concerning the study of human genetic diver- 
sity. It is reasonably clear to me that this planning process has not yet succeeded 
in devising an incisive set of goals and objectives, a convincing rationale, and a clear 
set of immediately achievable goals. This can clearly be achieved, but at the moment 
the plans remain immature. The important point, however, is that when the sci- 
entific questions and the ethical and social issues are properly dealt with in plan- 
ning this research, the project should be considered only on its own merits, and cer- 
tainly as distinct from the HGP. If this planning is done well, the project may well 
contribute substantially to understanding our biological heritage and our history — 
invaluable contributions to human knowledge. This represents another area that the 
HGP can contribute to by providing the fundamental resource for human diversity 
research. 
Conclusion 

The Human Genome Project, the historic, coordinated, international effort to map 
and sequence the genetic material of our species, is well underway and is making 
great progress. There are many reasons that this enterprise was undertaken; its ul- 
timate utility should extend to every branch of biological science, medicine, and bio- 
technology. Profound questions about human biology, human origins, human devel- 
opment, and human disease, will become answerable. To accomplish this in a rea- 
sonable time period and with the anticipated efficiency, which results from adher- 
ence to a careful plan, we must focus our attention and our resources on the goals 
at hand. The beneficiaries of the HGP will be every branch of biology and medicine. 
I support the broad aims of those interested in human genetic diversity studies and 
encourage them to make use of the powerful tools, resources, and vast knowledge 
deriving from the Human Genome Project. However, these studies should compete 
for funding on their own merits and should not be a part of the Human Genome 
Project. 

This concludes my prepared testimony. I would be happy to answer your ques- 
tions. 

Senator Akaka. Dr. Nishimi? 

TESTIMONY OF DR. ROBYN NISHIMI, SENIOR ASSOCIATE, BIO- 
LOGICAL AND BEHAVIORAL SCffiNCES PROGRAM, OFFICE 
OF TECHNOLOGY ASSESSMENT 

Dr. NISHIMI. Thank you, Mr. Chairman. 

I appreciate the opportunity to appear before you to discuss the 
issues raised by the Human Genome Diversity Project. My written 
testimony presents a general overview of this project and a broad 
identification of the technical, funding, and ethical, legal and social 
issues that it might raise. I will focus my oral testimony on sum- 
marizing matters related to funding and to ethical, legal and social 
implications. 

The Human Genome Diversity Project, as you have heard, is a 
proposed and unfunded effort. A congressional role is important be- 
cause, even at this early stage, it is obvious to OTA that the project 
is unlikely to move forward in any coordinated fashion without 
some Federal funding. 

Such funding might derive from three sources: NSF, NIH, or 
DOE, singly or in collaboration. It appears to OTA, however, that 
prior to Federal funding, an analysis is necessary to determine 
what level of funding is needed, how much is currently available 
from reprogramming of existing NSF, NIH or DOE funds, and 
what new appropriations might be necessary. 



16 

Scientists proposing the project estimate its cost at about $25 
million over 5 years. OTA has neither analyzed nor verified this es- 
timate. 

With respect to ethical, legal and social issues, I would like to 
highlight a few questions. First, many of the populations proposed 
for sample collection are in developing nations. What if certain 
data gathered prove commercially valuable? Developing countries 
have already expressed concerns about patent issues, such as those 
spotlighted by the Rio de Janeiro summit in the context of intellec- 
tual property protection for novel plant and animal material and 
the "Biodiversity Treaty." Not surprisingly, concern is heightened 
by the prospect that the substance now in question is human bio- 
logical material from vulnerable populations. 

Beyond the legal issues of intellectual property protection are 
also ethical and social questions, and I will just focus on a few. 

For example, will any benefits of the research accrue to the re- 
search subjects? The issue of informed consent itself raises several 
questions. Informed consent expressed in whatever form is a mini- 
mum activity to demonstrate respect for a culture. Do Western no- 
tions of informed consent have any true relevance to some of the 
populations to be sampled? Yet, while Western notions of consent 
might differ drastically from those populations to be studied, the 
concept of respect surely persists. 

Clearly, any research conducted with Federal funds will need to 
comply with current U.S. regulations governing human subjects re- 
search. Yet these rules may conflict with the practices, values or 
beliefs in other societies. 

What about, for example, the U.S. practice of a written docu- 
ment? A written document is important because it endures as a 
record for the future, either as an instructive tool or for auditing 
purposes; yet written documents will be an anathema in some cul- 
tures. 

Similarly, Federal regulations require that a project's purposes 
be explained. One of this project's goals is to elucidate information 
about the origins of the sample population and its relationship to 
other populations. Some cultures, again, however, have deeply-root- 
ed beliefs about their origins and would find this goal offensive or 
insulting. Would it be ethical to emphasize certain goals — for exam- 
ple, identifying disease susceptibility — over others — for example, 
examining human origins — in order to merely facilitate consent 
and participation? 

Another example is the issue of obtaining informed consent from 
every individual in a community, or can a local leader or other 
central authority speak for all members? Consider a situation, for 
example, of a local leader who agrees to sampling for all members 
of his population, but researchers who are preparing to draw the 
blood from a woman plainly see that she is distressed by the pros- 
pect. Do they proceed, or do they decide not to sample? Will this 
now incur the leader's wrath because he has lost face, since he had 
given his word that all would participate? Will the woman now be 
overtly punished, or if not overtly punished, will this stigmatize 
her? 



17 

Analyzing ethical considerations is especially critical because 
many of the populations that have been proposed for sampling are 
groups that historically have been vulnerable or exploited. 
' Mr. Chairman, as was my task, I have focused on identifying is- 
sues that the Human Genome Diversity Project raises. Neverthe- 
less I think it is important to stress that despite the questions I 
have enumerated, OTA does not view this project either negatively 
or positively. Rather, I emphasize that OTA supports a thoughtful 
and deliberate discussion so that Congress can consider a full 
range of options. Clearly, a balance must be struck between our in- 
tellectual desire to pursue an exciting and interesting line of in- 
quiry against both our responsibility to devote research resources 
in the most efficient and prioritized manner, and more importantly, 
our ethical obligation to respect and enhance the welfare of all peo- 
ple. 

Thank you. I will be happy to answer any questions. 

Senator Akaka. Thank you very much, Dr. Nishimi. 

Prepared Statement of Dr. Robyn Y. Nishimi 

Mr. Chairman and Members of the Committee, I appreciate the opportunity to ap- 
pear before you today to discuss the opportunities and concerns raised by the pro- 
posed Human Genome Diversity Project. Some of these issues are related to the Of- 
fice of Technology Assessment's (OTA) ongoing study, "The Human Genome Project 
and Patenting DNA Sequences." This assessment, which I direct, is scheduled for 
delivery to the Technology Assessment Board in April 1994. 

I would like to emphasize at the outset, however, that my remarks will focus on 
the Human Genome Diversity Project, which is distinct and separate from the 
Human Genome Project. My comments will be a general overview of the Human Ge- 
nome Diversity Project and a broad identification of some of the issues that the 
project might raise. Currently, OTA is not conducting a full assessment of the 
Human Genome Diversity Project, as it did for the Human Genome Project in its 
1988 report Mapping Our Genes — The Genome Projects: How Big, How Fast? Never- 
theless, I anticipate that some of our current analyses for the "DNA patents" 
project — e.g., of intellectual property protection of DNA sequences and technology 
transfer issues in — will be pertinent to a few aspects of the Human Genome Diver- 
sity Project. As I will elaborate further, however, some issues raised by the Human 
Genome Diversity Project are beyond the scope of OTA's current study. 

BACKGROUND 

In humans, as in essentially all forms of life, deoxyribonucleic acid — DNA — con- 
tains the entire genetic blueprint for an individual. Today, scientists in the United 
States and abroad have undertaken the 15-year, $3 billion Human Genome Project. 
The result of this effort will be a single "reference" map of composite information 
that is essentially a Caucasian genome. Yet no two individuals, except identical 
twins, share the same DNA sequence. Furthermore, genetic diversity clearly exists 
among populations around the world. The Human Genome Diversity Project pro- 
poses a systematic examination of human DNA sequence variation by sampling 20- 
25 unrelated individuals from each of 400-500 populations of historical interest. It 
would be undertaken with the expectation that fundamental questions about the 
origins, settlement, and migration of humans could be examined. As well, the 
project could elucidate why some populations are more, or less, susceptible to cer- 
tain diseases. 

Discussion — and some early decisionmaking — on if, when, and how to undertake 
the Human Genome Diversity Project is a matter of some urgency: Several of the 
proposed research populations are literally becoming extinct. 

FEDERAL FUNDING 

The Human Genome Diversity Project is a proposed effort, for which its support- 
ers currently seek funding, and I would like to emphasize the importance of a con- 
gressional role: Even at this early stage, it is obvious to OTA that the Human Ge- 
nome Diversity Project is unlikely to move forward in any coordinated fashion with- 



18 

out some U.S. Federal funding. Scientists proposing the project estimate its cost at 
$23-25 million over five years; OTA has neither analyzed nor verified this estimate. 

Federal funding for the Human Genome Diversity Project might derive from three 
sources — singly or in collaboration: The National Science Foundation (NSF), the Na- 
tional Institutes of Health (NIH), or the U.S. Department of Energy (DOE). NSF 
is appropriate because it is the primary Federal agency that funds anthropology re- 
search, and most — but not all — of the questions that might be addressed by the 
Human Genome Diversity Project are anthropological in nature. NIH and DOE are 
appropriate because together they fund the U.S. Human Genome Project, and thus 
are familiar with the latest developments in genetic research. OTA has performed 
no analyses on funding structure or outlays for the proposed Human Genome Diver- 
sity Project. 

Since each of the agencies is represented at this hearing, I will not elaborate fur- 
ther on individual or joint capacities to fund the Human Genome Diversity Project. 
I note, however, that neither NIH nor DOE has included funding for the Human 
Genome Diversity Project in its current 5-year plans for the Human Genome 
Project. Hence, Congress would need either to appropriate additional funds to NIH 
and/or DOE for the Human Genome Diversity Project or instruct the agencies to re- 
direct existing funds to the diversity project — at the expense of investigations fund- 
ed under the auspices of the Human Genome Project. Further, I am not familiar 
with the details of funding for anthropological research through NSF and the extent 
to which NSF could fund this project — again solely or in cooperation with NIH and 
DOE. 

In sum, it appears that if the Human Genome Diversity Project is to receive Fed- 
eral funds, an analysis is required to determine what level of funds is needed to 
conduct the project, how much is currently available from reprogramming of NSF, 
NIH, or DOE funds, and what new appropriations might be necessary. 

TECHNICAL ISSUES 

The Human Genome Diversity Project presents several technical issues, which 
other witnesses can certainly address in greater detail. Briefly, some considerations 
include the following. 

• Although preliminary work has been undertaken to identify the populations for 
DNA sampling, Dr. Richard Ward, an anthropologist involved in the initial ef- 
fort raises concern that the criteria for identification vary among the groups, 
which were divided by geographic area. The issue is: What criteria should be 
employed to create a final sampling list to ensure that the project is consistently 
implemented? Then, does the current proposed list meet the criteria? 

• The project proposes to collect blood samples from indigenous peoples. Certain 
blood cells will be transformed into what scientists call "immortal cell lines." 
This process must occur within 72 hours of collection, but offers the advantage 
of largely preserving the genetic heritage of an individual in perpetuity. Never- 
theless, certain interesting genes — in particular those involved in immunity to 
disease — will not be amenable for analysis alter transformation; other DNA 
changes, currently unknown to scientists, might also be associated with trans- 
formation. Thus, besides collecting blood samples, what other biological material 
should be collected for DNA analysis (e.g., hair, cheek swabs)? From whom 
should this material be collected? Just the 25 individuals from whom blood has 
been drawn? Since interesting information can be derived from DNA samples 
alone, how many additional human research subjects are proposed for supple- 
mental sampling? 

• What biological material will be stored? How will it be stored? Who will manage 
access? Who will oversee quality control and quality assurance? Immortal cell 
lines require ongoing (in perpetuity) upkeep: Who will pay for these costs? What 
kind of databases will be used to manage the storage and retrieval of biological 
material? What about informatics for the information generated from the bio- 
logical material? As with the biological material, who will manage the informa- 
tion quality, access, and upkeep? 

• What minimum set of genetic markers should be analyzed for all samples? In 
what priority will samples be analyzed once a common set of markers has been 
identified? 

Although these are important questions, OTA's forthcoming report on patenting 
DNA addresses none of them. 



19 



ETHICAL, LEGAL, AND SOCIAL ISSUES 



The proposed Human Genome Diversity Project raises several ethical, legal, and 
social issues, and it is impossible to fully discuss them within the confines of my 
testimony. It is critical, however, that these issues be addressed. 

For example, many of the populations proposed for sample collection are in devel- 
oping nations. What if certain data gathered under the Human Genome Diversity 
Project prove commercially valuable? The United States must be sensitive to the 
concerns of developing nations, while simultaneously preserving legitimate interests 
of U.S. companies to pursue commercial development and intellectual property pro- 
tection of "biotechnological" products. Developing countries have already expressed 
concerns about the Human Genome Project and the general issues surrounding 
DNA patents. These concerns are similar to those that were spotlighted at the Rio 
de Janeiro summit last year in the context of intellectual property protection of 
novel plant and animal biological material and the "Biodiversity Treaty." Not sur- 
prisingly, however, they are heightened by the prospect that the substance now in 
question is human biological material from vulnerable populations. As Chaim Sheba 
of Israel has put it, "You have taken our gold and diamonds; now you are taking 
our genes." 

Beyond legal issues of intellectual property protection are several ethical and so- 
cial questions. 

• Will any benefits of the research accrue to the research subjects? 

• What are the risks — particularly social risks such as stigmatization — to re- 
search subjects who participate? To those who decline to participate? 

• What about compensation — monetary or otherwise — for research subjects? What 
if a country seeks payment in return for the collection of biological samples from 
its citizens? What if a local leader demands compensation? If compensating indi- 
viduals is an option, what happens to people not "chosen" as research subjects? 
What benefits realistically can be offered to participating communities, espe- 
cially if they are small and isolated? 

• What about confidentiality of the samples collected? What limits are necessary? 
Who decides? Who will be responsible for ensuring confidentiality? 

• In addition to collecting samples for the Human Genome Diversity Project, what 
about testing blood samples for disease? In particular, special attention to HIV 
infection is an issue — especially with blood samples from Africa, for example. 
Should samples be tested so that researchers can exercise greater caution when 
handling certain samples? Should the samples be tested anonymously to deter- 
mine infection rates in these populations? Is it ethical to test samples anony- 
mously? If it is unethical, then how does a demand to link a sample with an 
individual for purposes of disease identification balance against the importance 
of confidentiality for other purposes? If anonymous testing is viewed favorably 
and HIV testing is deemed desirable for the safety of scientists or to analyze 
HPV infection in indigenous populations, how will pretest counseling for HPv be 
handled on top of informed consent for the Human Genome Diversity Project, 

fenerally? 
he issue of informed consent raises its own questions: What constitutes mean- 
ingful informed consent in non-Western cultures? In fact, do Western notions 
of informed consent have any true relevance to some of the populations to be 
sampled? Nevertheless, informed consent, expressed in whatever form, is a min- 
imum activity to demonstrate respect for a culture. And while Western notions 
of consent might differ drastically from those of the populations to be studied, 
the concept of respect surely persists. 

Nevertheless, any research conducted with Federal funds will need to 
comply with current U.S. regulations governing human subjects research, 
in addition to adhering to any local governmental rules. U.S. regulations 
lay out eight specific informed consent requirements, and I will mention at 
least three that may result in conflict between U.S. regulations and prac- 
tices, values, or beliefs in other societies: a requirement for a written docu- 
ment, a clear explanation of the purposes of the research, and individual 
consent. 

A written document is important because it endures as a record for the 
future — either as an instructive tool or for auditing purposes. Yet written 
documents will be an anathema in some populations. How can this be rec- 
onciled with Federal regulations? 

Similarly, Federal regulations require that a project's purposes be ex- 
plained. One of the goals of the Human Genome Diversity Project is to elu- 
cidate information about the origin of the sample population, as well as its 
relationship to other populations. On face value, this might easily be put 



20 

in terms understandable to all cultures. However, some cultures have deep- 
ly rooted beliefs about their origins and would find this goal of the project 
insulting or offensive. What if this jeopardizes efforts to obtain samples 
from key communities? Would it be ethical to emphasize certain goals — e.g., 
identifying disease susceptibility — over others — e.g., examining human ori- 
gins — in order to facilitate consent and participation? Who decides? 

Must informed consent be obtained from every individual in a commu- 
nity? Can local leaders and other central authorities decide for all members 
of a community? Consider for example, a situation where a local leader 
speaks for all members of his group. What if he agrees to the sampling, but 
researchers who are preparing to draw blood from a woman plainly see that 
the woman is distressed by the prospect? Do they proceed? Do they decide 
not to sample her blood? Will this now incur the wrath of her leader, who 
has "lost face" because he had given his word that all would participate? 
Will she be punished overtly? If not overtly, will this stigmatize her? Should 
the investigators try to gain her individual consent? Is any consent she 
might then give truly consent, or has it been coerced? 

• If protocols vary (e.g., regarding compensation or consent) from culture to cul- 
ture, as might "be expected, who will arbitrate what's necessary to ensure the 
protection of the human research subjects? Will population-by-population ap- 
proval be necessary — especially if U.S. funds are used? If individual protocol re- 
view is deemed cumbersome by researchers, is there a reasonable expectation 
that all contingencies can be identified prior to embarking on sample collection? 

• What about issues of genetic discrimination? What is the best mechanism to 
minimize misuse and misinterpretation of the gathered data? In particular, 
since genetic differences are the proposed project's focus, concerns are raised 
about information being used to support notions of superiority of one group over 
another. Dr. Diane Paul, who has studied the social history of genetics, believes 
that the Human Genome Diversity Project is likely to reinforce conventional 
views of race and ethnicity. 

I have elaborated on ethical, legal, and social issues at some length, but by no 
means in an exhaustive fashion, f reiterate that analyzing these considerations is 
especially critical because many of the populations that have been proposed for sam- 
pling are groups that historically have been vulnerable or exploited. And while an- 
thropologists have dealt with some of these questions in their research for several 
years, the scale of the proposed Human Genome Diversity Project changes the dy- 
namics, as does the current international political context. 

The forthcoming OTA report on intellectual property protection for human DNA 
sequences will examine the question of patenting DNA, per se. However, it will not 
directly address the issue of property rights that might be sought from samples such 
as those that would be gathered under the Human Genome Diversity Project. It also 
will not analyze the ethical issues I have just touched on. 

THE OUTLOOK FOR THE HUMAN GENOME DIVERSITY PROJECT 

Mr. Chairman, as was my task, I have focused on identifying issues that the 
Human Genome Diversity Project raises and have not offered specific options to ad- 
dress them. Nevertheless, I think it is important in concluding my testimony to 
stress that, despite the many questions I have enumerated, OTA does not view the 
Human Genome Diversity Project either negatively or positively. Rather, I empha- 
size that OTA supports a thoughtful and deliberate discussion involving a broad 
spectrum of international perspectives, so that Congress can consider a full range 
of options. Clearly, a balance must be struck between our intellectual desire to pur- 
sue an interesting, exciting line of inquiry — one that may yield information about 
human origins, as well as medically important data — against both our responsibility 
to devote research resources in the most efficient and prioritized manner and, more 
importantly, our ethical obligation to respect and enhance the welfare of all peoples. 

Mr. Chairman, thank you for the invitation to discuss this important topic. I will 
be happy to answer any questions you or Members of the Committee might have. 

Senator Akaka. I thank all of you for your testimonies. They will 
be helpful. I have a number of questions for you and would like 
your responses. 

I think you know that the reason we are having this hearing is 
to get into the record some of the important data that can help us 
in the future as we continue to move the program and to try to get 
more funds than we have had in the past. 



21 

I would like to focus this hearing on the Human Genome Diver- 
sity Project, and its relation to the much larger Human Genome 

Initiative. . . . 

The study of the genetics of ethnic and aboriginal populations 
promises to answer many social and anthropological questions 
about mankind. That is what makes it exciting. I do not question 
the importance of that information. I believe, however, that Federal 
funding for such a project must be based on the potential for yield- 
ing tangible benefits for medical science. 

Let me direct my first questions to the DOE and NIH witnesses. 
In your testimony, you mentioned some of the benefits that might 
come from the study of diverse genomes. In what ways could such 
a project complement the current Human Genome Initiative? 

Dr. Galas, since you mentioned the relationship, I'll call on you 

first. 

Dr. Galas. I think it is very important to understand that the 
human genome, as we view it from the point of view of the Human 
Genome Project, is a very complex object because it represents, if 
you will, a map of all of our genetic blueprints, which differ from 
individual to individual, as the next panel will discuss in a little 
more detail. 

I think that the precise benefits to the Genome Project of the Di- 
versity Project depends on how you frame very specific questions. 
I don't think there is a general answer to that, because if you wish 
to answer certain questions about variations in certain genetic loci, 
or a certain type of variation in the genome between individual 
chromosomes or some such well-framed question, then you can an- 
swer the question that you ask — what is the potential complemen- 
tary benefit. 

It is certainly true that having diverse, different genomes to look 
at can be of potential interest to doing the very basic things, map- 
ping the humane genome. But unless those questions are framed 
in a very narrow and very critical way, I don't think that those 
questions can be answered. 

Dr. Collins. Can I address that as well? 

Senator Akaka. Please. 

Dr. Collins. The Human Genome Project has denned its goals 
carefully in order to be sure that the job gets done, and the project 
is aiming to develop maps, both genetic and physical, and to se- 
quence the human genome. The Human Genome Project does not 
intend itself to apply that information to all of the medical condi- 
tions that would be benefitted by such an approach. So, for in- 
stance, in the search that is going on right now for the breast can- 
cer gene, to a major extent the reagents and the maps that are 
being used for this process are products of the Human Genome 
Project. The utilization of those maps, however, to target that very 
specific breast cancer gene on Chromosome 17 is an effort that is 
also supported by other parts of the NIH (especially NCI), and 
should be. 

The Genome Project is there to build what we would loosely call 
infrastructure, to make it possible for projects like this to go for- 
ward. These would have been unthinkable without the rich array 
of resources that the project is now providing. 



22 

Similarly, I think the Diversity Project has goals in common with 
the Genome Project, and there are areas of significant overlap par- 
ticularly in technology development. The attempt to look at the 
DNA sequence of many different individuals, which is what the Di- 
versity Project needs to do, is similar to what needs to be done 
when you are looking at families in which a particular disorder is 
occurring, and you are trying to figure out what genes are respon- 
sible. So there are shared areas of interest which I think could be 
exploited. 

But in current terms, it would be difficult for the Genome Project 
to expand its umbrella to take on other more diverse efforts like 
the Diversity Project without expanding its funding. 

As far as the medical consequences of the Diversity Project, this 
is a difficult concept to think through. To what extent would hav- 
ing blood samples from 400 different ethnic populations help you 
understand why certain populations are predisposed to some dis- 
eases and others are not? Part of the answer comes down to what 
those genes are going to look like. 

Just to use an analogy, consider a group of people wearing dif- 
ferent colored sweaters. Let us suppose it is the people with the red 
sweaters who are somewhat more predisposed to getting a disorder, 
say diabetes, than the people who have green sweaters or blue 
sweaters or yellow sweaters. By comparing ethnic groups which 
have different proportions of red sweater wearers you might deduce 
the correlation. But that only works if there are a lot of people who 
wear red sweaters. If you are only looking at 25 people in each 
group, you need to have a fairly frequent finding in order to draw 
a conclusion. 

If, on the other hand, you are looking for a relatively rare gene — 
say, a red sweater with a blue collar — then 25 people may not in- 
clude one of those, and you may therefore not be able to draw any 
conclusions about why this particular population has a higher fre- 
quency of a particular disease. 

I do think we will learn things indirectly in either event about 
medical conditions, simply by finding out relatedness of popu- 
lations. If you find that this population has a high frequency of dia- 
betes, and another one does also, and then it turns out that they 
are related to each other, that implies to you that this is probably 
genetically programmed, especially if their environmental situation 
is very different; but it is a bit of an indirect argument. 

So I think it is really not easy to say right now what the solid 
medical consequences of the Diversity Project might be. They will 
occur. I am not exactly sure what they will look like and how 
quickly they will come along. 

Senator Akaka. The primary mission of the diversity study 
would be the collection and preservation of genetic information 
from several hundred — you point out 400 — ethnic and aboriginal 
groups that are near extinction. I use the word "extinction" loosely, 
and I am simply emphasizing that many of these populations are 
on the verge of losing their unique genetic identities. 

Do you feel there is merit in sampling ethnic and aboriginal pop- 
ulations while it is still possible, so that the information can be 
preserved for future investigators? I am still asking questions of 
DOE and NIH. 



23 

Dr Collins. I am happy to answer that question. Yes, I believe 
there is great merit. I do think the urgency is a compelling argu- 
ment, that populations are not going to be there indefinitely for us 
to decide at some future date we would like to sample them. 

So I do believe there is merit in the proposal. Obviously, that has 
to be couched with all the concerns about the ethical issues, which 
I think can be dealt with, but probably should be dealt with very 

The Diversity Project in its first three workshops has addressed 
those issues and has, I think, made a good initial review. I think 
it is very important that there be broad discussion of those issues 
and input from some of the countries that would be involved to be 
sure that the necessary safeguards are in place. 

Senator Akaka. Dr. Galas? 

Dr. Galas. I would agree, Senator, that there is certainly merit. 
So I guess I would agree in principal with what Francis said. It 
seems to me, however, that the devil is in the details, as we say, 
and that precisely what questions are being asked, or what we 
want to find out, will determine how the sampling is done, what 
sort of planning is carried out, and whether or not it is just sam- 
pling, or whether these people are to be looked at with respect to 
their genetic phenotypes as well. If you want to understand some- 
thing about the medical implications, you have to know something 
about the medical condition of the person from which these came. 

So these are questions that it seems to me need to be answered 
very precisely and very carefully before one can quantify the merit, 
however great it may be. 

Senator Akaka. It is always a pleasure to work with the talented 
scientists and engineers at OTA 

Dr. NlSHlMl. That's a dangerous lead-in. 

[Laughter.] 

Senator Akaka. You certainly make our job easier, we think. 
Thank you for being with us today. 

Dr. Nishimi. Thank you. 

Senator Akaka. We are all aware of the wonderful new treat- 
ments that might develop from the Human Genome Initiative. 
Have individuals from your agency studied the potential benefits to 
medical science that the Diversity Project might offer? If so, could 
you please detail for us what those benefits would be? 

Dr. Nishimi. OTA has not looked at the possibility of medical 
benefits from the Human Genome Diversity Project per se. We 
have looked at the Human Genome Project, but not the Diversity 

Project. 

Senator Akaka. What are the advantages of collecting DNA sam- 
ples for diverse populations? 

Dr. Nishimi. I think you have heard some of the benefits that 
might accrue from this project. I describe a few of those in my pre- 
pared statement — certainly, anthropological questions of human 
settlement patterns, migrations, and the like, and also the possibil- 
ity of certain medical benefits. But OTA hasn't done a detailed 
analysis of either approach, so I am afraid I cannot offer you more 
than just generalities. 

Senator Akaka. Do you feel that the Human Genome Diversity 
Project complements the goals and objectives of the larger Human 



24 

Genome Initiative, and how might the two projects work together 
to help ensure the overall success of both? 

Dr. NlSHlMl. Certainly, there are common elements, as Dr. Galas 
described, in terms of the Human Genome Diversity Project learn- 
ing from some of the Human Genome Project's technologies and 
being able to take advantage of those. I wouldn't like to offer, how- 
ever, any analysis on possible funding structure relationships be- 
tween NSF, NIH and DOE, or whether one agency should be the 
lead agency, because OTA, again, has not analyzed that question. 

Senator Akaka. The National Science Foundation has been a 
longstanding supporter of both hard and soft sciences, including 
anthropology and archaeology. I know that NSF supports several 
NSF Fellows studying anthropology. I am committed to the re- 
search opportunities offered by NSF, and I believe the educational 
benefits to the many supported students are a good investment by 
the United States. Thank you for being here today. 

Has NSF funded projects similar in scope or purpose to the 
Human Genome Diversity Project? If so, could you briefly outline 
the merits on which NSF based their decisions? 

Dr. Marrett. NSF has funded any number of projects that bear 
on this particular proposal. In fact, I appreciate this opportunity to 
comment on some of the observations that OTA has made in terms 
of the ethical and other questions. 

A number of those questions are in fact questions that are found 
in research, whether it happens to be on genetic diversity or not. 
One of the reasons why we have thought it very useful to combine 
the discussion of genetics with cultural and physical anthropology 
is that growing out of the research experiences particularly of cul- 
tural anthropologists has been an understanding of how to handle 
sensitive populations, sensitive matters. 

If one looks at the second of the workshops held, for example, 
that workshop said it would be extremely important to integrate, 
to sample in ways in which one could identify those populations 
from which we already had information about access, about the 
other sensitivities, populations on which we would have other 
kinds of medical information. So I would stress that what we are 
trying to do is to indicate that we would not be starting from 
ground zero; it would be building on the body of knowledge that is 
accumulated about particular populations and particular proce- 
dures to make sure that there is that sensitivity to the sets of is- 
sues that clearly must arise. 

Senator Akaka. Are you comfortable, Dr. Marrett, with the meth- 
odology of the Diversity Project and its dedication to minimizing 
the misuse of genetic information? 

Dr. Marrett. Let me start with what I would hope we would 
share with all of my colleagues from all of the Federal agencies, 
that we see our task first and foremost as promoting science, and 
in our case, science and engineering, for the advancement of hu- 
mankind. 

Having taken that position, then, it would be in fact inconsistent 
to support activities that seemed harmful to humankind. So with 
that as our first basis, we would say we would pay close attention 
to any matters that might in fact jeopardize the human population. 



25 

Beyond that, I would certainly support what my colleagues here 
on the panel have said— that there are matters still to be worked 
out. There are numbers of issues having to do with procedures to 
be developed. That is why, again, we continue to stress this as a 
proposal and not as a full-fledged project. Why we would see a par- 
ticular need and importance of linking in with the human genome 
organization is because of the expertise, the experience that has de- 
veloped, not only on the technological side, but on the fact that that 
organization has been grappling with in very serious ways the 
questions of ethical, legal, other matters. 

Hence, if you ask have all the issues been resolved so far, no, 
they have not been; they would be a part of the continued develop- 
ment that would be necessary if this proposal is to become a full- 
fledged project. . 

Senator Akaka. I thank this panel for your testimony. I could de- 
tect from each of you the concern about being very careful with the 
information that will be collected, and I hope that as we move 
along in positive directions, we can work on this. As new ideas 
come forth, in new areas, there is always the legal aspect to con- 
sider. We need to keep an eye on this as we move down the road. 

I want to say thank you very much for your testimony, Panel 1, 
and to tell you again that you have been very helpful. 

Senator Akaka. Let me now introduce Panel 2 and call to the 
table Dr. Luca Cavalli-Sforza, Professor Emeritus of Genetics, De- 
partment of Genetics, School of Medicine, Stanford University; and 
Dr. Mary-Claire King, Professor of Genetics and Epidemiology at 
the University of California at Berkeley. 

I welcome you here today and look forward to your testimonies. 
As soon as you are ready, you are welcome to begin, Dr. Cavalli- 
Sforza. 

TESTIMONY OF DR. LUIGI LUCA CAVALLI-SFORZA, PROFES- 
SOR EMERITUS OF GENETICS, DEPARTMENT OF GENETICS, 
SCHOOL OF MEDICINE, STANFORD UNIVERSITY 

Dr. Cavalli-Sforza. I am very pleased and honored to be able 
to testify on this important subject. I have spent much of my career 
in this field and now see the coming together of an urgent need for 
action and an increasing technological ability to take that action. 

In my spoken submission, I will briefly lay out what the HGD 
Project will do. It is made up of three main parts — first, the collec- 
tion of samples; second, their transformation and preservation, and 
third, their analysis. 

In previous workshops organized thanks to help from Federal 
foundations, we have started discussing with the experts of various 
disciplines statistical, anthropological, molecular, ethical and legal 
aspects of our work, and we will continue to refine our plans as 
necessary. 

We aim to collect a general sample of about 10,000 individuals 
representing the indigenous world population. This is the sample 
that Professor Francis Collins referred to before, but we also have 
planned to collect at the same time a larger sample of perhaps 
about 100,000 individuals, maybe 10 times as many, just for an- 
swering those questions that Professor Collins was rightly worried 
about that we might not be able to answer with the 10,000 sample. 



26 

The 10,000 individuals, which are the 400 populations with 25 
individuals each, will be treated in a more expensive way (by Ep- 
stein Barr virus transformation) to make them available forever, so 
to say; but the extra, 10 times as many, individuals will not be 
equally transformed, so it will be a much cheaper sample to collect 
and store, and they will answer all those questions that may come 
up in the meanwhile, especially problems of medical genetics also 
for rare genes. It is a much cheaper thing to collect the 100,000 in- 
dividuals sample once we have anthropologists in the field for col- 
lecting the smaller, more expensive samples. 

After the samples are brought to laboratories, they will be trans- 
formed by a technique developed for the purpose of obtaining in- 
definite amounts of DNA, a procedure largely employed since the 
beginning of the eighties in research on medical genetics. 

From 1966 to 1976, I have studied about 1,500 African pygmies 
in central Africa, and I returned in 1984 and 1985 to collect new 
samples. In collaboration with Yale University, these samples were 
transformed according to this new technique and were the first in 
a pilot project which now includes some 20 populations from all 
parts of the world. This gives us a guarantee that the project can 
be made. The samples from this collection have already been incor- 
porated in the Standard Repository of Cell Cultures set up by the 
National Institutes of Health General Medical Sciences at Camden, 
New Jersey and are being increasingly used by scientists. 

We have carried out extensive studies of the data collected on the 
populations prior to the DNA era and on those of the pilot project 
and believe that once new populations will be collected, their analy- 
sis should begin soon, as it could influence ways in which the 
project will be continued. In other words, we plan to learn from ex- 
perience as soon as we start collecting samples. 

New technology being developed for the Human Genome Project 
will soon become available, we hope, and will certainly be ex- 
tremely useful. It is our desire to keep in close contact with that 
project at all levels, from molecular to data analysis, and to main- 
tenance of databases. Cell lines, DNA results, are not intended as 
a private reserve, but must be available to every scientist. The cost 
for access to these resources should be assessed in the best interest 
of science and society. 

What can we expect to find? There are historical, anthropological, 
medical implications. Professor Mary-Claire King will speak about 
the last ones. In a book of mine on the history and geography of 
human gene, which is an analysis of what is already known, and 
which is to appear before the end of this year, there is a summary 
of conclusions obtained from the analysis of thousands of publica- 
tions that have appeared so far, mostly generated in the pre-DNA 
era. The transition to DNA technology has greatly amplified the 
power of the genetic approach but has not contradicted the results 
that we have already obtained. These remain the most powerful 
scientific tool we have against racism, as summarized in my writ- 
ten testimony. 

Conclusions of the most recent studies have raised considerable 
interest among scientists of many disciplines, also outside the field 
of genetics, ranging from history and archaeology to anthropology 
and linguistics. 



27 

I have been amazed especially by the excitement among laymen. 
I have been overwhelmed by the volume of correspondence I have 
received. It is clear that this work will help educators to spread 

Eublic knowledge of science and create new interest for it. It is a 
eautiful example of how exciting science can be. It will also gen- 
erate more understanding of genetic differences between individ- 
uals and between groups, which are very small compared to those 
between individuals of one group, as well as of the rights of indige- 
nous people. One should not forget that public awareness can be 
very beneficial to indigenous populations, who continue to be 
abused even today in many countries. But it is essential that the 
information be accurate, or it could be counterproductive. 

Whether for science or for humanitarian purposes, it is important 
that the field work be carried out by scientifically-trained anthro- 
pologists. This is a major departure that we propose with respect 
to previous collection of these data. 

We must not forget that it is urgent to undertake this work be- 
fore economic development completely destroys or confuses the cul- 
tures and identities of those populations. Just to give a few exam- 
ples, in Tierra del Fuego, there are left two or three descendants 
of the Ona tribe, if any, and perhaps two dozen of the Alacaluf 
nearby. These are people who were there at the time Charles Dar- 
win visited the area. Only a few dozen individuals from four Ne- 
grito groups survive in the Andaman Islands and have very low 
fertility. There are extremely few children. How many, if any, will 
there be at the turn of the century? We cannot afford to wait. 

Thank you. 

Senator Akaka. Thank you very much, Dr. Cavalli-Sforza. 

Prepared Statement of Dr. L. Luca Cavalli-Sforza 

1. The general aims of the HGD Project 

The Human Genome Diversity (HGD) Project aims to survey the genetic diversity 
of living humans. It proposes to do so by sampling primarily indigenous populations, 
whose origin is usually better known than that of individuals who emigrated in the 
past centuries to new places. These samples will come from an adequate number 
of individuals representing the human species and will be used to form a repository 
ensuring unlimited survival of their genetic material, DNA, for future study. Spe- 
cial, but not exclusive, attention will be paid to peoples of historical interest who 
are likely to disappear through physical extinction or, more frequently, dispersal 
and loss of identity. These events are taking place at an alarming rate, parallehng 
the rates of economic development and habitat destruction that cause them. The 
Project is therefore urgently needed in order to avoid the irreversible loss of precious 
human genetic information. 

2. Storage of cell lines 

The HGD Project makes use of the existence of modern techniques of cell con- 
servation, which allow us to keep certain cells of an organism alive and capable of 
multiplying, thus generating potentially unlimited amounts of the organism s DNA. 
Almost no DNA deterioration is experienced under these conditions. For this pur- 
pose, fresh samples of blood must be collected and transported shortly after collec- 
tion to appropriately equipped laboratories, where certain blood cells (B 
lymphocytes) are transformed by Epstein-Barr virus. The cells are then grown and 
stored on liquid nitrogen, where they conserve indefinitely their viability and capac- 
ity to multiply. This is a well-tested, standard procedure. There has also been a pilot 
project, which has accumulated a small number of samples of individuals from in- 
digenous populations of various continents for research use. 

3. Choice of populations and other technical problems 

We have held three workshops with support from the National Institutes of 
Health (NIH), the National Science Foundation (NSF), and the Department of En- 
ergy (DOE)— in July 1992 at Stanford University, October 1992 at Pennsylvania 



28 

State University, and February 1993 at the NIH campus in Bethesda. These work- 
shops have helped us form a preliminary opinion of the major problems at the sta- 
tistical, anthropological, molecular, bioethical, and social levels. Final proceedings of 
these workshops have been or are being prepared, and we are in the process of 
forming working groups to continue the analysis. Appropriate choices of populations 
and individuals are an essential part of the Project, and to this end we have enlisted 
the cooperation of an international array of anthropologists. With their help, we 
have established a preliminary list of about 400 to 600 populations to be sampled. 
On the basis of discussions with population geneticists and statisticians, we plan to 
generate transformed cell lines from about 25 unrelated individuals in each popu- 
lation. Anthropologists already working with the population generally will obtain 
the blood samples for the preparation of transformed cell lines. In addition, we ex- 
pect the anthropologists to collect blood, saliva, or hair samples from at least ten 
times as many individuals in the same and related, neighboring populations. These 
latter samples will not be subjected to transformation, but will De stored for special 
studies requiring larger numbers of individuals for which smaller, limited amounts 
of DNA are sufficient, and for which methods of DNA amplification that are less 
sophisticated, and less expensive, than Epstein-Barr virus transformation can be 
employed. 

4. Extent of diversity of the human genome 

It would be wrong to think that the human genome exists in a single copy, re- 
peated again and again in every individual. The opposite is true; one can say that 
there are as many human genomes as there are humans, and the potential variety 
of human genomes is on the order of one followed by one million zeros, an extremely 
high number. It is very unlikely that any living human beings have exactly the 
same DNA. Even identical twins differ from each other, because after duplication 
of the fertilized egg giving origin to both of them, a dozen or more fresh mutations 
are expected to occur. 

Prompted by the enormous magnitude of the task of analyzing the whole human 
genome, the Human Genome Project was started, in its simplest form, to study a 
single copy of the genome (not necessarily all coming from the same individual). Our 
lab is involved in research on two genetic diseases. We are well aware of how useful 
it would be and how much time we would save if we had the preliminary informa- 
tion on the DNA sequence in even one individual. 

It is true, however, that our lab and others will gain a number of important bene- 
fits from a better understanding of individual variation. An important step forward 
can be made in the next 5 years with an expenditure that is a very small fraction 
of the annual cost of the Human Genome Project per year. The time is now ripe 
for starting an adequate analysis of diversity; and the optimal procedure is to begin 
it as soon as possible in concert with the sampling of disappearing indigenous world 
populations. 

5. Why study individual diversity? 

It is easier to appreciate the general importance of studying individual DNA vari- 
ation if one considers that the real purpose of studying the sequence — the structure 
of the human genome — is to infer the function of its parts. This constitutes a consid- 
erable challenge. We cannot today accurately predict the function of a DNA segment 
by simply determining its sequence; we can only make some informed guesses. The 
study of variation of a DNA segment among individuals can, however, contribute in 
an important way to understanding its function. In general, genes that are basic to 
the life of the cell or of the individual vary very little from one individual to the 
other and only in specific ways, which affect only trivially their function. Lack of 
variation, or its minimal presence, indicates an "important" gene; changes in it are 
likely to determine serious abnormalities. For this reason, the study of genetic dis- 
eases can contribute in a major way to understanding the function of a gene. In fact, 
the identification of a gene responsible for a disease usually requires detection of 
a clear association between changes in its structure and specific pathological phe- 
nomena. More generally, the function of a gene is understood by making with as- 
sumptions about the specific function influenced by the gene together with a study 
of the variation among individuals of the DNA structure. Although some of this 
work can be carried out in test tubes, knowledge of individual diversity remains es- 
sential to truly understanding the ways genes function. 

6. Some general guidelines for the study of diversity 

Five years after the beginning of the Human Genome Project, the task of sequenc- 
ing a smgle genome still appears formidable, and it is thus far premature to think 
that one could, or would want to, completely sequence even just two genomes, which 
might seem the minimum necessary for learning about individual diversity. But 



29 

there are rapid technological advances that should ensure progress in a few years, 
and what appears today an impossible task may well be far less difficult a few years 
from now. It is also certain that the technologies being developed for study ot the 
human genome are ideally suited for the analysis of individual diversity and that 
there will be considerable reciprocal fertilization at the technological level between 
the developments in the mainstream Human Genome Project and the Human Ge- 
nome Diversity Project. And, after all, the applications of the HGD Project to medi- 
cal genetics, which are one of the main justifications for the Project, are merely spe- 
cific instances of individual variation. At least initially, however, it is neither fea- 
sible nor necessary to study individual variation for the whole human genome. 

Rather than studying all individual variation in the entire human genome, we 
need to set up methods and learn rules that allow us to predict the individual vari- 
ation to be expected in a given segment with minimal effort. This can be done by 
studying individual variation in a sample of DNA segments; this sample need not 
be large. I mentioned the rough guiding principle that the more important the func- 
tion of a DNA segment, the less variation is seen in that segment among individ- 
uals. But this principle is not general enough. There exist DNA regions for which 
individual diversity is a biological necessity. We study the HLA genes, for instance, 
because of their importance to the success of organ transplantation and to the pre- 
disposition to certain autoimmune diseases. One could say that these HLA genes 
help a body know what is part of it. Here, extreme individual variation is essential 
for the HLA complex to work. 

Because of its cost, the analysis of DNA samples from the world's population for 
the purpose of studying individual diversity can be extended by present methods 
only to a small fraction of the whole human genome. But the study should be 
planned so as to make that fraction as informative as possible. Let us assume that 
we want to analyze 10,000 DNA segments of a convenient length in different parts 
of the genome. They should be chosen to represent various categories of genes and 
DNA segments, which we can already identify to some extent. Although, ideally, 
they would be studied for all of the roughly 10,000 individuals from whom cell lines 
will be prepared, in Its early stages the analysis should be restricted to a smaller 
fraction of individuals (for example, a well-balanced mini-sample of 100 to 1,000 in- 
dividuals). The mini-sample could be chosen in such a way as to represent the world 
through a hierarchical stratification of the 10,000 individuals. It would thus be easy 
to evaluate the usefulness of extending the survey of individual variation for a par- 
ticular segment to all the 10,000 cell lines, or even to the 100,000 or more DNA 
samples from the non-transformed collection. Only those DNA segments that show 
sufficient variation would be eligible for study on the larger samples. The majority 
of them would not have to be sequenced, just tested with cheaper methods allowing 
the recognition of individual "polymorphic'' (variable) sites. The collection of indige- 
nous populations could be organized so that after the first year, it would constitute 
a "mini-sample" of individuals and populations adequate for coverage of the whole 
world. This mini-sample then could be employed for the initial screening of vari- 
ation. 

A very small collection of cell lines from all over the world is already in existence 
and is being used in preliminary observations, thanks to a pilot project set up in 
the last few years by the writer in collaboration with Professors Ken and Judy Kidd 
of the Genetics Department of Yale University. Samples of this collection are avail- 
able to all research workers through the Camden Repository of New Jersey. But the 
mini-sample to be used for initial assays should be a better representative of the 
world than the one currently available. 

Even with analysis of individual variation limited to a small fraction of the 
human genome, a general picture can be obtained that will help direct further in- 
vestigations. We currently know very little of individual variation at the DNA level, 
but we are aware of the existence of some segments that are much more variable 
than others. We are bound to find more with a systematic search. The variation in 
these segments seems to have a precise biological meaning, and it will be important 
from a biological point of view to establish whether the high variation is due to high 
rates of mutation, natural selection, or other mechanisms. In my view, the search 
for highly variable DNA segments should have the highest priority because these 
segments are the most informative, but it will take time to detect them. A first 
phase of extensive preliminary investigations must therefore be dedicated to choos- 
ing appropriate, representative DNA segments to be studied. Neither in this initial 
phase nor in later ones will it be necessary to use full sequencing methods on all 
individual samples for each DNA segment; cheaper and faster methods would be 
preferable at least for initial screening, especially in regions in which variation is 
usually low. 



30 

It is my belief that research workers engaged in genome research will in due time 
find an inexhaustible source of important new biological problems in the study of 
individual variation. The HGD Project will take great advantage of, and also con- 
tribute in an important way to, the current trends toward automation of DNA se- 
quencing and, especially, toward testing individual genetic variation of medical im- 
portance. Our rapidly increasing arsenal of research robots can speed up consider- 
ably the testing of large numbers of individuals for specific DNA segments, but we 
first need to learn more about the extent, location, and causes of individual vari- 
ation, and more about optimal strategies for studying diversity. 

7. The need to study variation throughout the world 

Individual variation must be studied on a world sample, and not on a limited 
sample of individuals collected locally, as has been the case so far, because there 
exists intergroup as well as intragroup variation. We have recently demonstrated 
that limiting the study of variation to Caucasoids, as has been done in almost all 
the investigations of DNA variation, has introduced a serious bias in the evolution- 
ary interpretation of the data. Moreover, the full power of the study of individual 
variation would not be harnessed if the study were limited to Caucasoids. There is 
considerable ethnic variation in genetic disease and predisposition to disease, which 
is important in planning health surveys, providing dietary advice, searching for do- 
nors for transplants, and so on. 

It is thus necessary to explore the whole human species with a well-designed sam- 

Kling scheme. At the same time, it is necessary to avoid the dispersion of effort that 
as characterized most work carried out in the pre-DNA era, in which different re- 
search workers studied haphazard collections of variable genetic characters on arbi- 
trarily chosen populations. As a result of this lack of coordination of the earlier 
work, today one can obtain only an extremely patchy set of data from the published 
work. The information that can be obtained is a very small fraction of what it would 
have been if the immense effort of the thousands of research workers who volun- 
teered their effort had proceeded in a more organized manner. A collection of cell 
lines made available to research workers in a central repository can help to avoid 
this waste by preserving a limitless supply of particular DNA samples to be ana- 
lyzed. It will still be necessary, however, to ensure that some of the testing effort 
be made in a systematic way. By making available to researchers, at especially low 
cost, a set of cell fines chosen so as to be a representative world sample, the Project 
could help ensure a more balanced and informative effort. 

I will concentrate here on giving a short account of scientific benefits that this 
endeavor can generate for the study of the history of human differentiation and evo- 
lution. We had already accumulated substantial knowledge on the genetic variation 
of human populations before the DNA era. But this information suffers from many 
uncertainties and from having been almost entirely unplanned and being therefore 
full of gaps, which make its analysis difficult and inefficient. Even so, we now know 
that the study of living populations allows the reconstruction of important aspects 
of human history. These reconstructions already have helped to explain archaeologi- 
cal, historical, and linguistic data. Striking conclusions have thus been reached, 
which have received wide interest, but which need confirmation and extension. Mod- 
ern methods of studying individual diversity using DNA have much more power 
than older methods and can examine a much greater range of genetic variation (po- 
tentially all). They are much more efficient and precise and can be more easily auto- 
mated than the older techniques; considerable efforts in this direction are already 
under way. Increasing the number of populations and the number of genes (DNA 
segments) studied thus far will lead to enormous increases in the variety of histori- 
cal problems one can approach. Moreover, the analysis of DNA allows us to obtain 
"fossil" information, previously unattainable, from mummies, bones, and other an- 
cient material. For the full use of fossil information, however, one needs to have 
adequate data on living populations from the same and neighboring areas, with 
which the fossil data can be compared. 

8. Bioethical and social problems 

Perhaps the most substantial question that arose in our workshop on bioethical 
and social problems is whether the study of intergroup genetic difference might fos- 
ter racism. I am persuaded that it will have the opposite effect. It is difficult to do 
I'ustice to this important subject in a short time, but more extensive analyses can 
>e found elsewhere. It might be useful to begin by a definition of racism, which in 
my view is the belief that differences in the success of different peoples or races are 
due to their inherent biological superiority or inferiority. The idea is that this supe- 
riority is genetically determined and, as such, is inherited and impossible to change 
(notoriously, the superior race is almost always one's own). The importance of 
sociocultural inheritance in determining success (whether economic, political, or 



31 

military) is usually forgotten. All empires are of short duration, suggesting imme- 
diately that the background to success is socioeconomic and cultural; it cannot be 
genetic, because genetic processes are much slower, and very little genetic change 
can take place in the few centuries during which empires rise and fall. This is a 
very simple but powerful consideration that is not, however, heard frequently, sim- 
ply because knowledge of genetic processes is confined to a few specialists. 

Another consideration about racism is that genetic differences between human 
groups are small. We already have considerable information from a study of genetic 
markers with methods of the pre-DNA era. We have still-limited information on 
intergroup diversity using data obtained directly from DNA, since the relevant tech- 
niques have become available only in the last decade, but we already know enough 
to be confident that the picture thus obtained is very similar to the older one, but 
much more clear. The basic conclusion from the study of differences among groups 
is that they are small compared with the differences within the groups themselves. 
The aspiration to "race purity" of classical racism is absurd. A village or a small 
tribe will show almost the same extent of genetic variation among individuals as 
will the whole world. Only human populations of very small islands that have been 
subjected for a long time to very close inbreeding (marriage among close relatives) 
show a moderate increase in genetic homogeneity. This increase is often accom- 
panied by infertility, as would be expected from the conclusions of countless animal 
(and to some extent plant) breeding experiments. 

The statement that genetic differences among races are very small may seem to 
fly in the face of evidence known to everybody. If we look at skin, eye, or hair color, 
or the facial and body morphology of people who originated on different continents, 
we can usually predict their ethnic origin accurately, simply relying on these super- 
ficial traits. Most such characters are homogeneous within the groups and snow 
sharp differences between the groups. This is iust the opposite of what we conclude 
from a random, large sample of genes studied with either pre-DNA or DNA meth- 
ods, where almost without exception differences between people from the various 
continents are quantitative, not qualitative, and of small magnitude with respect to 
genetic differences within groups, even in small towns or villages. For genes existing 
in various forms, one usually finds that the same forms exist in almost all parts 
of the world, but only in different percentages, and the differences in the percent- 
ages are rarely striking. Clearly, skin, eye, and hair coloration and the shape of the 
human face and body are not randomly distributed genes, and they show much 
greater racial differentiation. It seems important to discuss the reason for this dif- 
ference, which is clear even if it is not widely known and which can explain this 
apparent contradiction. Everything we see and use in our diagnosis of ethnic origins 
of individuals in every day is a property of the surface of the body. Humans origi- 
nally developed in the warmer parts of Earth and only later, in the last 50,000 
years or so, spread to the rest of the world. They even had to learn to survive in 
extremely cola environments, such as Siberia. This involved a cultural as well as 
a biological adaptation. All the characters that show a strong difference between 
races, as well as greater homogeneity within races, are connected with adaptation 
to climate, and have been so explained by physical anthropologists. It is inevitable 
that they involve the surface and general shape of the body, because those aspects 
of people form the interface between the external world, from whose physical rigors 
we must protect ourselves, and the internal one, the temperature or which we try 
quite successfully to keep constant. 

It is not surprising, therefore, that the surfaces of our bodies differ greatly de- 
pending on the climates in which our ancestors developed in the last tens of thou- 
sands of years. As the surface is the part of us that we see, its conspicuousness af- 
fects our judgment on questions of race, and prompts us to believe that all other 
differences are equally striking. But the truth is that they are not. We may add that 
they could hardly be, given that the evolutionary separation among humans living 
on the various continents has been relatively short; there just has not been time 
to develop much genetic divergence among humans. 

Knowledge about our real, and very limited, genetic differences can only help to 
defuse the "race bomb." It is, however, obvious that any data can be misused and 
abused. The best protection is education based on solid facts and research. 

9. The plight of indigenous populations 

Many indigenous populations live in conditions of extreme poverty, many are 
being abused and victimized in the process of economic development. Their plight 
is usually well hidden, and it is very difficult to help them. The United Nations is 
aware of the urgent needs of many indigenous populations and has called 1993 the 
year of the indigenous people. Given the many terrible, urgent problems that face 
the world today, the limited resources of the United Nations are fully committed in 



32 

many parts of the globe. It is unrealistic to hope that this agency could do much 
to help indigenous populations. 

The HGD Project might help indigenous populations in at least two ways. First, 
the Project's investigations may make the burdens borne by particular populations 
public knowledge. The Project can also generate greater public knowledge and inter- 
est in cultural diversity and the desirability of maintaining it. It would of course 
be impossible to reach all populations in need in the course of the Project; there are 
about 5,000 different populations in the world, based on the count of different lan- 
guages in existence, and the Project can reach about ten percent of them. 

10. The HGD Project and identity 

The HGD Project has generated enormous spontaneous interest among journalists 
and laymen. The program has the potential for discovering remote origins of people, 
if not or not always for individuals at least for groups, and this seems to evoke 
strong, positive, emotional reactions. Most people know too little about their remote 
past, Decause, after their ancestors migrated to America, their family lost its collec- 
tive memory of its previous country as a result of the ignorance and the anger that 
often accompany the poverty and oppression that forced many of them to abandon 
their homes. But knowledge of personal identity may be a basic interest of humans 
and an important component of self-esteem, and information of the kind that the 
program can provide may be cherished by many. It is well known that several cul- 
tures dedicate special effort to conserving their genealogies. 

11. Spreading scientific knowledge 

A further consideration is that the Human Genome Diversity Project can contrib- 
ute to spreading interest in genetics among the public and may create a desire to 
learn more about our science. Greater scientific literacy should be one of our coun- 
try's most important goals to prepare our population for the future. Recent inter- 
national comparisons show this is a major and urgent need in the United States. 
The Human Genome Diversity Project will generate further knowledge of the kind 
promoted by the Human Genome Project, but it will also generate curiosity in many 
individuals, some of whom would not be interested in the Human Genome Project. 
This curiosity may become a powerful stimulus to additional interest in the life 
sciences, which are often taught in high school and will, I hope, become even more 
popular. My colleagues and I cannot forget — and policy makers should not forget — 
that science can be extremely exciting. The way the Human Genome Diversity 
Project connects with people interested in history, anthropology, languages, family 
roots, or a wide variety of topics outside molecular biology offers a wonderful oppor- 
tunity for public education. The Project will give proper attention to that oppor- 
tunity. 

Senator Akaka. Dr. King? 

TESTIMONY OF DR. MARY-CLAIRE KING, PROFESSOR OF GE- 
NETICS AND EPIDEMIOLOGY, UMVERSITY OF CALIFORNIA 
AT BERKELEY 

Dr. King. Thank you, Senator. 

It is both an honor and a great pleasure to be asked to speak 
with you today about the Human Genome Diversity Project. As you 
have heard from my colleagues, the revolution in genetics offers us 
now the unprecedented opportunity to unlock many of the secrets 
of biology. 

In the area of medical research, mapping and sequencing the 
human genome will enable us to solve the mysteries of many 
human diseases that have so far eluded us. As you know, my own 
passion in this area is breast cancer, from which women of native 
Hawaiian ancestry suffer the highest rates in the world. 

As Dr. Collins told you, he and I and our young colleagues have 
every hope of identifying very soon the gene responsible for inher- 
ited breast cancer. We will know when we have found the culprit 
gene because the sequence of that gene will be different for women 
who have inherited breast cancer compared to women who have 
not. 



33 

How do native Hawaiian women with breast cancer differ from 
other women in their sequences of this gene? We don't know yet. 
I think we should sample native Hawaiian women and find out. 

Differences in genetic sequences between people are revealing 
the causes of many common human diseases. All of us have the 
same genes. However, we often have slightly different sequences of 
those genes. Most of these differences have no impact on our lives, 
but a few do. Genes that cause terrible diseases can differ from 
their normal counterpart genes by very subtle differences—often 
only one or a few base pairs of DNA out of thousands. But the con- 
sequences of that variation can be immense. Where does this ge- 
netic variation come from? Why has it persisted? What does it 

mean? 

Our genetic differences are at the very heart of our evolution as 
a species. One of the most fascinating paradoxes of the human con- 
dition is that we are all different, yet we are all the same. If I take 
a sample of my DNA and compare it to the DNA of another person 
selected at random from anywhere in the world, she and I will be 
the same for perhaps 999 base pairs out of 1,000, and will differ 
maybe at one. Because each of our cells contains 6 billion base 
pairs of DNA, those differences add up. There are millions of dif- 
ferences between two randomly selected people. But 99.9 percent of 
our DNA is the same. 

Of course, if I select my brother and compare my DNA to his — 
hardly a random selection— he and I will be much more similar 
than two unrelated people; in fact, my brother and I will be iden- 
tical for some DNA sequences. 

The genetic identity of people in the same family has enabled us 
to bring justice to victims of human rights violations. Specifically, 
working with human rights groups in Argentina, my lab takes ad- 
vantage of the genetic identity of specific DNA sequences among 
relatives to identify families of children who were kidnapped and 
whose parents were killed by military forces in Argentina during 
the Dirty War. 

Working now with the U.S. Army Central Identification Labora- 
tory in Hawaii, my lab is using exactly the same tools to identify 
MIAs from the Vietnam War. This approach only works because we 
previously analyzed the genetic diversity of the same DNA se- 
quences. In other words, we can only establish a person's genetic 
identity by knowing how unlikely it would be for two unrelated 
people to be exactly the same for a long sequence of DNA. 

At the other extreme from a brother and sister, if I select people 
from two populations that have been isolated from each other for 
most of human evolution, they will differ by more than 1 in 1,000 
base pairs. But it is important to note that this variation does not 
follow the social concepts of race we grew up with. And under- 
standing genetic diversity as it really exists can provide irrefutable 
evidence against racial stereotyping. 

Dr. Cavalli was too modest to tell you, but his work dem- 
onstrated some 30 years ago that if one samples all of the residents 
of a small village of pygmies in central Africa, one will find in that 
small village virtually all of the genetic variation that one would 
find by taking a sample of the entire world. 



34 

Roots and origins are fascinating, but what can genetic variation 
tell us about the human condition today? Let me return to Africa 
for a medical example. Sickle cell anemia is the most common ge- 
netic disease among African Americans. We know a great deal 
about the genetics of sickle cell anemia, because it was possible to 
study this disease at the level of the hemoglobin protein and the 
red blood cell. Of course, most common diseases do not leave such 
good clues at the protein and cellular levels. That is why we need 
information from our genes, and that is why we need the Human 
Genome Project. 

Until very recently, sickle cell anemia killed its victims as chil- 
dren or young adults. So why does it still exist? Why didn't the 
sickle cell gene die out with its victims? As any young biology stu- 
dent will tell us, sickle cell anemia continues because people who 
carry the sickle cell gene are protected against malaria. It only 
takes one copy of this gene to protect a child against malaria, but 
it takes two copies for a child to develop sickle cell anemia. 

Malaria has killed more people in human history than any other 
disease. So when a DNA sequence appeared in human evolution 
that protected children against the most powerful killer in their 
midst, that gene flourished, even though two children protected by 
that gene might grow up and have a child together who inherited 
a sickle cell gene from each of them and died of sickle cell anemia. 

Now, how was this complex story of hemoglobin, sickle cell ane- 
mia, and malaria disentangled 50 years ago? It was not done by 
studying modern African Americans. Malaria no longer exists here. 
Rather, the puzzle was solved by studying indigenous populations 
from areas of Africa where malaria had been common since the be- 
ginning of agriculture and where people had lived in relative isola- 
tion since that time. 

The correspondence between malaria and sickle cell anemia 
among populations in central Africa was very strong. Populations 
with high rates of malaria also had high rates of sickle cell anemia. 
We now know at the genetic level that people with sickle cell ane- 
mia have a specific mutation in a hemoglobin gene. 

The point of this story is that sickle cell anemia was understood 
by studying the ancestral African populations from which modern 
African Americans are descended and by analyzing the genetic var- 
iation among those African populations. 

I would tell you the story of blindness on the island of, but I real- 
ized this morning that you know more about it than I do, so I will 
go on. 

The Human Genome Diversity Project is still evolving. We still 
have a great deal of work to do. In the past year, our evolution has 
been quite rapid as a project. We have developed an administrative 
and scientific infrastructure for the project and have held three 
workshops. You have heard about these workshops from Dr. 
Marrett. The first was devoted to mathematics; the second to an- 
thropology, which populations best represent our common human 
ancestry, which are in most danger of extinction, what are the lin- 
guistic relationships among these populations? 

Very importantly, in this country, our indigenous ancestral popu- 
lations are not only subjects of the study, but also coworkers, 
whose participation is crucial for our success. Their cultural and 



35 

linguistic resources will allow us, in fact, to work successfully on 
Native Americans in the project. Representatives of Native Amer- 
ican tribes have contacted us and asked to participate collectively 

in the work. , , 

The third workshop at Bethesda was the longest and was de- 
voted to ethical, legal and social implications of the project. How 
are the rights of people who blood samples to be protected? What 
is informed consent under these circumstances? How can we pro- 
vide open access to materials for researchers and at the same time 
protect against misuse? 

These same issues faced us and continue to face us as researches 
in the larger Human Genome Project. We look forward to working 
with our colleagues in the Human Genome Project in trying to un- 
derstand and address these very thorny subjects. 

I would particularly call your attention to the report of the work- 
shop on ethical, legal and social issues, prepared by Professor Hank 
Greely from the Stanford University Law School. It is included 
with your materials. That workshop established a committee struc- 
ture consisting of four subcommittees— on collection, social implica- 
tions, review and evaluation for the Human Genome Project. Of 
particular interest was the concept of a set of rapid-response com- 
mittees that could address possible misuse of genetics, both from 
the Diversity Project and generally, should such allegations arise. 

The second issue we addressed at the Bethesda workshop was 
how to select genetic markers which will provide the most scientific 
information for the questions we want to answer. This addresses 
some of the concerns that were raised by my scientific colleagues 
a few minutes ago. 

The third issue at the Bethesda workshop was the question of 
how the Diversity Project complements the research interests and 
programs of the National Science Foundation, the National Insti- 
tute of General Medical Sciences represented here this afternoon 
by Ruth Kirschstein, and the Human Genome Project. 

We enthusiastically support a review and discussion of the 
Human Genome Diversity Project by the National Research Coun- 
cil and look forward to working with the Human Genome Project 
personnel on ethical, legal and social issues shared by both 
projects. 

In closing, let me pose a few of the fascinating and important 
questions of human experience that can be addressed by studying 
human genome diversity. 

When people have the same exposures to viruses or bacteria, why 
do some get sick and others not? 

Are high blood pressure and diabetes common now in some 
American populations because genes for these conditions were an 
advantage in ancestral populations earlier in human evolution? 

How do people migrate? How did humans move out of Africa? 
Were the Americas settled in waves or in streams? How was Ha- 
waii settled? By whom? How do languages and cultures move with 
people? 

In summary, the genetic diversity of living humans reflects the 
evolution of our species. We believe we can link molecular analysis 
of the human genome with population genetics, anthropology, ar- 
chaeology and linguistics to study our past and present. The goal 



36 

of the Human Genome Diversity Project is to understand who we 
are as a species and how we came to be. 
Thank you. I'd be delighted to answer questions. 

Prepared Statement of Dr. Mary-Claire King 

It is both an honor and a great pleasure to be asked to speak with you today 
about the Human Genome Diversity project. As you have heard from my colleagues, 
the revolution in genetics offers us now the unprecedented opportunity to unlock 
many of the secrets of biology. In the area of medical research, mapping and se- 
quencing the human genome will enable us solve the mysteries of many human dis- 
eases that have so far eluded us. My own passion in this area is breast cancer, from 
which, as you know, women of native Hawaiian ancestry suffer the highest rates 
in the world. As Dr. Collins told you, he and I and our young colleagues have every 
hope of identifying, very soon, the gene responsible for inherited breast cancer. We 
will know when we have found the culprit gene, because the sequence of that gene 
will be different for women who have inherited breast cancer compared to women 
who have not. 

Differences in genetic sequences between people are revealing the causes of many 
common human diseases. All of us have the same genes. However, we often have 
slightly different sequences of those genes. Most of these differences have no impact 
on our lives. But a few do. Genes that cause terrible diseases can differ from their 
normal counterpart genes by very subtle differences — often only one or a few base 
pairs of DNA out of thousands. But the consequences of that variation can be im- 
mense. Where does this genetic variation come from? Why has it persisted? What 
does it mean? 

Our genetic differences are at the very heart of our evolution as a species. One 
of the most fascinating paradoxes of the human condition is that we are all different, 
yet we are all the same. If I take a sample of my DNA and compare it to the DNA 
of another person selected at random from anywhere in the world, she and I will 
be the same for about 998 base pairs out of 1000 and will differ at only two. Because 
each of our cells contains 6 billion base pairs of DNA, those differences add up to 
millions between two randomly selected people. But 99.8 percent of our DNA is the 
same. Of course, if I select my brother and compare my DNA to his (hardly a ran- 
dom selection), he and I will be much more similar than two unrelated people. In 
fact, my brother and 1 will be identical for some DNA sequences. 

The genetic identity of people in the same family has enabled us to bring justice 
to victims of human rights violations. Specifically, working with human rights 
groups in Argentina, my lab takes advantage of the genetic identity of specific DNA 
sequences among relatives to identify families of children who were kidnapped and 
whose parents were killed by military forces in that country during the Dirty War. 
Working with the US Army Central Identification Laboratory in Hawaii, my lab is 
now using exactly the same tools to identify MLAs from the Vietnam War. This ap- 
proach only works because we previously analyzed the genetic diversity of the same 
DNA sequences. In other words, we can only establish a person's genetic identity 
by knowing how remarkable it would be for two unrelated people to be exactly the 
same for a long sequence of DNA. 

At the other extreme from a brother and sister, if I select people from two popu- 
lations that have been isolated from each other for most of human evolution, they 
will differ by more than 2 in 1000 base pairs. It is important to note that this vari- 
ation does not follow the social concepts of race we grew up with, and understanding 
genetic diversity as it really exists can provide irrefutable evidence against racial 
stereotyping. Let me explain. Some very interesting work has been done with DNA 
sequences from people of African ancestry, people of European ancestry, and people 
of Native American ancestry. DNA sequences from two randomly selected African 
individuals will differ from each other more than an African's sequence will differ 
from a Caucasian European's sequence or a Native American's sequence. That is, 
there is more genetic variation within Africa alone than there is between Africa and 
anywhere else. Why? Because human evolution has its most profound depth in Afri- 
ca. As a species, we have lived longest there. Fundamentally, we are all African. 
Understanding our genetic roots reveals our common human origin. 

Roots and origins are fascinating, but what can genetic variation tell us about the 
human condition today? Let me return to Africa for another medical example. Sickle 
cell anemia is the most common genetic disease among African Americans today. 
We know a great deal about the genetics of sickle cell anemia, because it was pos- 
sible to study this disease at the level of the hemoglobin protein and the red blood 



37 

cell. (Most common diseases do not leave such good clues at the protein and cellular 
levels. That is why we need information from our genes.) 

Until very recently, sickle cell anemia killed its victims as children or young 
adults. So why does it still exist? Why didn't the sickle gene die out with its victims? 
As any young biology student will tell us, sickle cell anemia continues because peo- 
ple who carry the sickle cell gene are protected against malaria. It takes only one 
copy of the sickle cell gene to protect a child against malaria, but it takes two copies 
of the sickle cell gene for a child to develop sickle cell anemia. Malaria has killed 
more people in human history than any other disease. So when a DNA sequence 
appeared in human evolution that protected children with one copy of it against the 
most powerful killer in their midst, that gene flourished, even though two children 
protected by that gene might grow up and have a child together who inherited a 
sickle cell gene from each of them and died of sickle cell anemia. 

How was this complex story of hemoglobin, sickle cell anemia, and malaria dis- 
entangled 50 years ago? It was not done by studying modern African Americans. 
Malaria no longer exists here. Instead, the puzzle was solved by studying indigenous 
populations from areas of Africa where malaria had been common since the begin- 
ning of agriculture and where people had lived in relative isolation since that time. 
The correspondence between malaria and sickle cell anemia among populations in 
central Africa was very strong. Populations with high rates of malaria also had high 
rates of sickle cell anemia. We now know at the genetic level that the people with 
sickle cell anemia have a specific mutation in a hemoglobin gene. The point of this 
story is that sickle cell anemia was understood by studying the ancestral African 
populations from which African Americans were descended and by analyzing the ge- 
netic variation among those African populations. Only among these ancestral popu- 
lations who lived and still live in geographic areas where malaria was so devastat- 
ing was the sickle cell gene an advantage, even though in a double copy, it was le- 
thal. The ancestral populations provided the critical clues, and proteins were the 
critical molecules. Ancestral populations still provide critical clues, with molecular 
evidence now coming from our genes. 

The Human Genome Diversity project is still evolving. We still have a great deal 
of work to do. In the past year, our evolution has been quite rapid. We have devel- 
oped an administrative and scientific infrastructure for the project and have held 
three workshops. The first workshop, at Stanford, California, was devoted to mathe- 
matics. How many samples need to be gathered and how many DNA sequences or 
markers need to be typed for each person? The second, at University Park, Penn- 
sylvania, was devoted to anthropology. Which populations best represent our com- 
mon human ancestry? Which are in most danger of extinction? What are the linguis- 
tic relationships among these populations? 

The third workshop, at Bethesda, was the longest and was devoted to three is- 
sues. First were the ethical, legal, and social implications of the project. How are 
the rights of the people from whom a blood sample is requested to be protected? 
What is informed consent under these circumstances? How can we provide open ac- 
cess to materials for researchers and at the same time protect against misuse? I 
would particularly call your attention to the report of that workshop prepared by 
Professor Hank Greely from the Stanford University Law School, which is included 
with your materials. Second was the question of selecting the genetic markers which 
will provide the most scientific information for the questions we want to answer. 
The third issue at the Bethesda workshop was the question of how the Human Ge- 
nome Diversity project complements the research interests and programs of the Na- 
tional Science Foundation, the National Institute of General Medical Sciences, and 
the Human Genome Project. We have been working with these agencies and believe 
the Human Genome Diversity project reflects the commitment to biological anthro- 
pology at the NSF, contributes to the development of resources that has been so his- 
torically important at the NIGMS, and can both contribute to and take advantage 
of technological developments in rapid typing and sequencing and in data base man- 
agement at the Human Genome Project. 

In closing, let me pose a few of the fascinating and important questions of human 
experience that can be addressed by studying human genome diversity. When peo- 
ple have the same exposures to viruses or bacteria, why do some get sick and others 
not? Are high blood pressure and diabetes common now in some American popu- 
lations because genes for these conditions were an advantage in ancestral popu- 
lations earlier in human evolution? How do people migrate? How did humans move 
out of Africa? Were the Americas settled in waves or streams? How was Hawaii set- 
tled? By whom? How do languages and cultures move with people? 

In summary, the genetic diversity of living humans reflects the evolution of our 
species. We can link molecular analysis of the human genome with population ge- 
netics, anthropology, archaeology, and linguistics to study our past and present. The 



38 

goal of the Human Genome Diversity Project is to understand who we are as a spe- 
cies and how we came to be. 

Senator AKAKA. Thank you very much, Dr. King. Both of your 
testimonies will be helpful to us. 

I will address the following questions to the panel as a group. 
The agency witnesses have raised some very interesting points that 
I believe need to be addressed. I will prepare some written ques- 
tions on this topic which I will ask you to answer for the record. 

Representatives from various Federal agencies have highlighted 
their position on the importance of the Diversity Project. This is an 
opportunity for you to demonstrate that the Diversity Project rep- 
resents a commitment to advancing medical science. My question 
is: How might the Diversity Project help medical researchers un- 
derstand why different populations are susceptible to different dis- 
eases? 

Dr. King. It is well-known among epidemiologists and medical 
researchers that in some populations, a particular disease will be 
very common, whereas the same disease in other populations will 
be very rare. 

For example, in parts of Finland which have been genetically iso- 
lated for a long while, myocardial infarction is very common. If we 
can understand why that is true at the level of our genes, that in- 
formation will inform us not only about heart disease in Finland, 
but also about heart disease for all of us. The biology of the disease 
is the same. But we have the particularly good fortune to be able 
to pinpoint populations in which genetic influences on the disease 
both occur and are frequent. 

Isolated populations are particularly valuable for this purpose. 
As Dr. Collins mentioned, one needs a larger sample than just 25 
individuals from each population in order to carry out such an 
analysis fully. That is why we propose to select a few individuals 
from each population from whom we would like to make permanent 
access of DNA available; but many more individuals from each pop- 
ulation so that we can close in on exactly these specific questions 
as they arise. 

Senator Akaka. Can you cite examples of how the study of ances- 
tral populations have increased our understanding of health prob- 
lems afflicting modern Americans? Do you suggest that the study 
of the genetics of ancestral populations might shed light on medical 
issues that are relevant today? 

Dr. King. Sickle cell anemia is an interesting example of how the 
investigation of a disease in ancestral populations can tell us a 
great deal about why that disease is so common in America today. 

Another example might be the investigation of the autoimmune 
disease systemic lupus erythematosus, which is very common 
among Americans of African ancestry and among Americans of Ha- 
waiian and other Pacific ancestries, but is less common among 
Americans of European ancestry. If we can investigate the genes 
responsible for susceptibility to that disease in the Pacific and in 
Africa, we will learn a great deal about the underpinnings of that 
disease generally and will have much better tools for diagnosis and 
treatment of it. 

Senator Akaka. Very interesting. The Human Genome Project 
under the sponsorship of NIH and DOE has tried to establish a 



39 

single reference genome. This reference genome will be made up of 
many individual DNA samples, but would not contain the level of 
diversity that you advocate. What medical science opportunities 
might be overlooked if the Human Genome Diversity Project does 
not proceed? 

Dr. Cavalli-Sforza. This is where we still don't know enough to 
give a totally satisfactory answer, but we can give examples that 
already show that it is going to be very important. What little we 
know about human variation from one individual to another shows 
that it is very different, depending on the particular part of the ge- 
nome being analyzed. There are parts of the human genome that 
are almost invariable from one individual to another. They usually 
are important in the sense that if they vary, the individual may be 
dead or severely sick. So that knowledge is important from a medi- 
cal point of view. 

But there are also other parts of the genome that are found to 
vary some time considerably from one individual to another. We 
know that some vary without detriment, but others must vary for 
individuals to function normally. And recently variation was de- 
tected which might have seemed trivial, but it turns out that it 
may be responsible for important diseases, one of which is Hun- 
tington's Chorea. 

Senator Akaka. Preservation of genetic data of near-extinct pop- 
ulations is an important issue that I believe warrants further ex- 
amination. Would you say that a primary component of your pro- 
posed study is the collection of genetic samples from cultures that 
are vanishing? Why does this project need to be done now? Why 
the urgency? 

Dr. Cavalli-Sforza. We are observing, because of economic de- 
velopment of Third World countries, an enormous increase in mi- 
gration, and also disappearance of populations living in peripheral 
locations, and very frequently in marginal conditions. The increase 
in communication and the opportunities of working abroad are cre- 
ating enormous changes in human customs and peoples distribu- 
tion and admixture. 

If we want to reconstruct populations history, and understand 
under what conditions certain diseases became prevalent in a popu- 
lation, we have to study these things now, before complete confu- 
sion. So I believe that we really have to start being active very 
soon. 

Senator Akaka. The Human Genome Project currently funds re- 
search that investigates the legal, ethical and social implications of 
their ongoing genetic studies. What measures do you feel must be 
taken to ensure that a diversity study is sensitive to the concerns 
of the various ethnic groups about privacy and racial stereotyping? 

Dr. King. There are three classes of issues here, all difficult. I 
might call those issues rights, royalties and racism. 

In the area of rights, the question is: What constitutes informed 
consent in isolated populations? In this area, we confront the same 
concerns that confront us in working in the larger Human Genome 
Project. We will establish a procedure for model protocols for work- 
ing with populations from widely diverse cultures so that standards 
that are coherent with the culture are employed for the projects we 
hope to undertake. 



40 

It is absolutely critical to us that representatives of the cultures 
that we hope to investigate be part of this process; that people not 
simply be the subjects of studies, but participants in them. 

In the area of royalties, we need expert advise. Dr. Greely is in 
the process of working with legal experts in ownership of informa- 
tion questions and how those apply to the Third World. 

On the question of racism, I must tell you that I entered human 
genetics because the question of race and IQ reared its ugly head 
in Berkeley when I was a graduate student there, happily working 
in theoretical statistics. I realized that it was simply not possible 
to be a scientist in a vacuum. 

That specific question may plaque us less now, but the overall 
question of racism and the misuse of genetic information as racist 
propaganda is certainly still with us, and nowhere is that more ob- 
vious just now than in Europe. 

We need to balance in research generally and in this project in 
particular the need for openness of information and open access to 
resources without censorship against the danger of misuse. 

I am not sure any of us will ever have the perfect solution. An 
open society leaves open the possibility of demagoguery. One ap- 
proach that we discussed at the workshop is to have ready re- 
sponse committees available, people who can be called upon in ge- 
netics, in social sciences, in law and in ethics, at a moment's notice, 
to address outrageous claims if they arise. 

We do not wish to shut off access to information, but we most 
certainly wish to put debate about these concerns into their proper 
scientific perspective. 

Senator Akaka. Does the Human Genome Diversity Project have 
a position on Federal funding and support for the Human Genome 
Project? 

Dr. King. The Human Genome Project is proceeding remarkably 
rapidly, despite having been underfunded since its inception. It is 
going more quickly than anticipated based on full funding, and it 
has done so on far less than full funding. 

It is essential that the core goals of the Human Genome Project 
proceed as originally scheduled. 

What we hope to do is integrate the goals of this project with the 
goals of the Human Genome Project, particularly in the area of 
technology development, and in addition to obtain funds that will 
enable both sets of goals to be carried out more rapidly. From our 
point of view, it is essential that both the larger Human Genome 
Project and the far smaller Human Diversity Project be more fully 
funded so that we can get answers to these questions while it is 
still possible to do so. 

Senator Akaka. The President has launched his technology ini- 
tiative to help the United States regain our competitive edge in 
many high-tech industries. A key component of the initiative is 
education. How will the Human Genome Diversity Project contrib- 
ute to public education about genetics? 

Dr. Cavalli-Sforza. As I already indicated briefly in my presen- 
tation, I believe that the Human Genome Diversity Project is a per- 
fect example for education in genetics, because people are very in- 
terested in their origins and history. The Project offers a natural 
way to bring them to want to study the subject of genetics. 



41 

There already exists one example that has been very successful. 
The Musee de l'Homme has started an exhibition in which it ex- 
plains human individual diversity and racial diversity. This exhi- 
bition has had enormous success and has travelled to many other 
parts of Europe where, as I am sure you know, there have been ex- 
plosions of racism which are becoming very worrisome to many of 
the governments. 

I might add perhaps a few words on what you were asking before 
about racial stereotyping. The real diversity we find is between in- 
dividuals within a group, but not so much between groups. We are 
misled by an unfortunate fact, in that we see just the surface of 
people, the surface being skin color, and the size, and the general 
body shape and facial shape, etc. But that has been designed by 
natural selection to respond to differences in climate, and it does 
not respond to any other thing, except it is the only thing we see. 
So from the fact that blacks are black, whites are white, et cetera, 
more or less uniformly, we argue that every other trait is equally 
uniform between races, but this is absolutely wrong, and this is the 
message we already know very well and should be made much 
more widely known. We also know it is not going to be contradicted 
by the DNA data, because we already have a substantial amount 
of information from DNA confirming what we already know from 
pre-DNA studies. If we make this known on a very wide scale, we 
will really help to eliminate at least some of the prejudices that ac- 
company and cause racism. 

Senator Akaka. I liked the remarks made by Dr. King and your- 
self about educating people like me. To find something that will 
unlock the secrets of genetics is fascinating, and something that de- 
fines the evolution of our species is very interesting. It is an amaz- 
ing project that you are engaged in. 

Finally, as scientists, what do you feel is the most important dis- 
covery that we can learn from the Human Genome Diversity 
Project? 

Dr. Cavalli-Sforza. Maybe summarizing what I was saying, we 
can learn that we individually are extremely diverse; as groups, we 
are not as diverse as we think we are; we are much more similar, 
and our kinship is extraordinarily high. But also from that individ- 
ual diversity, we may learn something useful for an orientation to- 
ward our best behavior in terms of our nutrition, in terms of our 
protection against diseases, and this will require learning more 
about our individual diversity. 

Senator Akaka. Do you have any remarks on that, Dr. King? 

Dr. King. As always, Luca is a very hard act to follow. I think 
the understanding of how we are all the same and yet, all different, 
will enable us to understand a great deal about why we are dif- 
ferentially susceptible to different diseases. In particular we can 
learn how genetic susceptibility and environmental exposures 
interact with one another for many of the most acute viral diseases 
that we confront today. 

Senator Akaka. I want to thank you and the other witnesses for 
participating in today's hearing. I would rate the hearing a success, 
and I say that because I believe we have learned a great deal— I 
have — about the scientific merits of the Human Genome Diversity 
Project. I have a better appreciation for the Diversity Project and 



67-460 - 93 - 4 



42 

feel that the Federal Government should strongly consider support- 
ing this project. I hope that my colleagues will feel the same when 
they read the record and learn more about what you have said. 

I am confident that concerns about the misuse of genetic data 
collected during the study will remain a central concern to the Di- 
versity Project team members. I stress that the effort to avert ra- 
cial bias and stigmatization must remain a primary concern for 
both projects. 

I hope that the agencies present for today's hearing will seriously 
consider the benefits that the Diversity Project offers. The Diver- 
sity Project is motivated by the urgency, as expressed here, to col- 
lect the genetic samples before it is too late. 

I will review the information gathered today and will closely fol- 
low developments related to the Human Genome Project and the 
supplemental Human Genome Diversity Project. Again, I thank all 
the witnesses for your excellent testimonies and recommendations. 
The Committee will keep the record open for ten working days to 
receive additional written testimony. 

If there are no further questions or comments, then this con- 
cludes today's hearing. The Committee will stand in recess subject 
to the call of the chair. 

[Whereupon, at 3:42 p.m., the Committee was adjourned.] 



APPENDIX 



The Pennsylvania State University 

University Park, PA, April 30, 1993. 

Hon. Daniel Akaka, Senator 
Washington, DC 

Attn: Shane Merz 

Dear Senator Akaka: Everyone knows the poignancy of extinction. Natural his- 
tory museums around the world exhibit specimens of extinct beings. The only rem- 
nant we have of many species are a few specimens collected in the past few cen- 
turies by dedicated naturalists, and we are grateful to them for preserving those 
specimens, and to our museums for making them available to us — and to posterity. 
It is all we have left to see, to remember. 

Something similar applies to our own species. Human populations around the 
world are systematically being absorbed into the greater mass of large national pop- 
ulations, their ethnic and biological identities disappearing forever. One aim of the 
Human Genome Diversity project is to collect and preserve for posterity adequate 
samples of the unique genetic variation found in and between the diverse popu- 
lations of our species. 

Such data can help anthropologists, linguists, archeologists, and human biologists 
to reconstruct the history and pre-history, settlement origins, and ethnic patterns 
of different regions in the world, and to understand the kaleidoscope of our 
similarities and differences. These are the anthropological objectives of the Human 
Genome Diversity Project. 

If our country has entirely lost its will to do basic science — things done for inter- 
est and for their own sake — we will lose our leading place in current world science, 
and our noble place in world history of science, and will rightly be blamed by gen- 
erations of our children for thinking only of our own immediate, selfish, material 
interests. 

However, if the effort to preserve our species' genetic patrimony, with all of its 
diversity, is important for its own sake, there are also immediate practical benefits 
to the HGD project. 

Human genetics is making incredible strides in our understanding of the genetic 
factors that are involved, to a greater or lesser extent, in nearly every human dis- 
ease. We owe much to the efforts associated with the Human Genome Project. But 
if there is one thing we are learning from that Project, it is that even for the sim- 
plest diseases there is a large amount of variation within any human population: 
cases of the same disease in different individuals are caused by different genetic 
variants and, importantly, different genetic variants produce clinical differences in 
the disease, and these can be important in treatment, prevention, and prognosis. 

Within a given population, a few variants are involved in most of the cases, but 
a substantial number of other rarer variants are also found. Where we have ade- 
quate data, even closely related populations (e.g., different European nations) can 
have largely nonoverlapping sets of causal variants for a given disease. Only after 
we have studied a population thoroughly, and know its specific variants, can we 
work on the treatment approaches relevant to each, and do effective risk counseling. 

Moreover, different ethnic groups have different genetic variants for the same dis- 
ease, and sometimes these do not overlap at all. We have a lot of data on Euro- 
{ jeans, Japanese, and so on, that is, about people living in wealthy places with major 
aboratories. But how do we understand the risk of disease in other groups? Even 
if we know the gene and its function, we must search each ethnic group separately 
to identify that group's disease-causing variants. 

This country has among its citizens numerous people from all but the smallest 
and most isolated human populations. Our big cities like New York and Los Ange- 

(43) 



44 

lea, and our states, like Alaska, Arizona, and Hawaii, are inhabited by very diverse 
populations, and these include large numbers of people with admixed ancestry 
among different populations. One need think only of Mexican-Americans, with Euro- 
pean-Amerindian ancestry, or African-Americans, to remember that there are tens 
of millions of these people in our population. In aggregate, they may soon comprise 
the majority of our citizens. For various diseases, these people are subject to risks 
that differ, probably at least in part for genetic reasons, from the risk in the better- 
studied part of our nation. 

The National Institutes of Health mandates affirmative action in all of its re- 
search grants, to ensure that all of our nation's people are served by the research 
and clinical establishment. How is it that we can allocate vast sums of money to 
studying human genes in a way that specifically excludes consideration of relevant 
diversity? 

The organization (and a representative sequence) of our genome can be docu- 
mented any time and without urgency. We will benefit greatly from this being done. 
But many peoples in the world are facing inevitable loss of their genetic integrity 
as populations. A worldwide sampling of human genetic diversity, including rare 
and endangered populations as well as the major ethnic groups, would cost only a 
trivial fraction of the amount being spent to understand the organization of the ge- 
nome, would preserve this variation for posterity. 

The core of the proposed Genome Diversity Project can document this diversity 
in general terms. A subset of larger samples, or even disease-related screens, fo- 
cused on those populations that comprise our major ethnic groups (proper represen- 
tation of Africans, Amerindians, Pacific and Asian populations, Indians, etc.), can 
provide biomedically critical data. 

These biomedical objectives are important aspects of the Human Genome Diver- 
sity idea. But I think it is just as important that the project, with its inherent, so- 
cial, historical, and ethnic interest, can help preserve for American science a sem- 
blance of scientific inquiry that is rapidly being lost amid the ever more blatant 
scramble for funding to do immediately 'relevant' work. 

This letter itself represents part of the sad need we face in today's science to de- 
vote large fractions of our time to seeking funds, and to try to justify the expendi- 
ture. I think our country should again make room for scientific inquiry that is justi- 
fied because it is interesting — that is what drew most of us to scientific careers in 
the first place. It is the basis of our scientific research and training infrastructure, 
and the seed-bed for new ideas. It is willingness to nurture free curiosity that made 
this country the scientific envy of the world. 

If I can provide you with more specific information and ideas about the Genome 
Diversity initiative, please let me know. 
Yours truly, 

Kenneth M. Weiss, Ph.D. 
Professor of Genetics & Anthropology 
Head, Department of Anthropology 



Answers to Questions from Senator Akaka 

After hearings of the Senate Committee on Government Affairs concerning the 
Human Genome Diversity Project (the "HGD Project"), held on April 26, 1993, Sen- 
ator Daniel K. Akaka asked Professor Henry T. Greely on behalf of the HGD Project 
Organizing Committee and particularly its two witnesses before the Committee, 
Professor L. Luca Cavalli-Sforza and Professor Mary-Claire King, to respond for the 
record to several written questions. These materials provide the answers sought, as 
well as commenting on a few other matters of note concerning the HGD Project. The 
HGD Project Organizing Committee is grateful for this opportunity, and the oppor- 
tunity afforded by the hearings themselves, to expand Congressional and public 
knowledge of this exciting scientific endeavor. We would be happy to answer any 
further questions concerning the HGD Project. 

Question 0. 1. Please outline the immediate goals and objectives of the Human Ge- 
nome Diversity Project. 

Answer. The goal of the Human Genome Diversity (HGD) Project is to help us 
better understand our species through collecting, preserving, and analyzing genetic 
material from diverse populations around the world. 

The investigation of individual genetic variation in the groups studied will have 
the following objectives: 

a) to help reconstruct the history of the world's populations, including important 
demographic events such as major migrations and expansions; 



45 

b) to obtain information of potential or actual medical interest for epidemiological 
objectives, directed to the health and welfare not only of the individuals or groups 
sampled but also of the rest of the world; 

c) to explore, as far as is practical, biological problems such as, for example, the 
functions of genes or the adaptations of humans to different environments, as well 
as to provide a resource for future work on these points; and 

d) to provide a basis for comparisons with similar data on DNA from archaeologi- 

To achieve these aims, the Project will undertake the collection of biological sam- 
ples from a number of human indigenous populations, paying special attention to 
endangered groups but also including appropriately sampled individuals from less 
remote areas, in order to obtain a balanced picture of human genetic variation. At 
the very beginning of the Project, some of the samples may come from indigenous 
populations that are relatively easy to reach (for example, in North America), but 
the most endangered populations will be considered as early as possible. 

Second, the Project needs to begin the transformation and preservation of the 
samples. White blood cells collected from an adequate number of individuals will be 
transformed and stored using a technique that can provide essentially unlimited 
amounts of DNA, so that they can immediately be used for research and also pre- 
served for future studies. Without transformation, the value of the collections would 
be greatly limited. We plan to store transformed cell lines at the Coriell Institute 
for Medical Research in Camden, the existing cell-line facility established by the 
NIH Institute for General Medical Sciences (NIH-GMS). 

DNA thus collected will be made available for analysis to interested scientists, 
and every attempt will be made to ensure that the use of this material will be as 
efficient and as scientifically valuable as possible. Results of DNA analysis will be 
stored in appropriate data bases available to scientists. 

The HGD Project is in the process of completing its organizational structure and 
planning. This includes forming committees to oversee the collection, storage, and 
analysis of samples. It will also ensure the stimulation of similar initiatives in other 
countries and parts of the world and coordination and cooperation with them. There 
is a European HGD Project that has already received initial funding from the Euro- 
pean Economic Community. Another committee structure will address the ethical, 
social, and legal issues in depth. 

Three workshops held in the past ten months in preparation of the HGD Project 
have been financed by the National Science Foundation, the National Institutes of 
Health, and the Department of Energy. While the planning for the science and orga- 
nizational structure is proceeding, the Project is also searching for funding. 

Question 1.1. What criteria should be employed to create a final sampling list to 
ensure that the Human Genome Diversity Project is consistently implemented? 

Answer. The HGD Project will give highest priority to indigenous populations that 
are more likely to disappear because of actual extinction or absorption into other 
groups and to isolates of historical interest. Frequently, these two criteria apply to 
the same population. The collection should not be limited exclusively to these 
groups, and tne survey should eventually represent all the world's indigenous popu- 
lations as fully as possible from geographic, ethnic, and linguistic points of view. In 
collaboration with 55 anthropologists at the second planning workshop, we have 
generated a list of about 500 populations of special interest. These represent roughly 
one-tenth of those that can be recognized as linguistically distinct. This list is ten- 
tative and may be adjusted as the work proceeds. 

We should start casting our net on the whole world in a systematic way by spac- 
ing locations to be sampled so that, even if they are not exactly equidistant from 
one another, the most important regions and people will be sampled first. In this 
way, in a short time we can develop an approximately representative world survey, 
which can be sequentially improved. The initial, sparse network of locations will 
thus be filled progressively, making use of the information and experience as it ac- 
cumulates from the survey itself. Some priority will be given to populations in the 
United States, both to test the collection routine under less difficult conditions and 
to reassure other countries that American researchers have done the same research 
with American indigenous populations. 

Question 1.2. Besides collecting blood samples, what other biological material 
should be collected for DNA analysis? Should this material be collected from just 
the 25 individuals from whom blood was drawn? Since useful information can be 
derived from DNA samples alone, how many additional human research subjects are 
proposed for supplemental sampling? 



46 

Answer. Transforming white blood cells in order to obtain indefinite amounts of 
DNA is an expensive procedure. Our plan, based on discussions and consensus from 
the first workshop, is usually to limit transformation to about 25 individuals per 
population. Non-transformed genetic material is much less expensive to store. The 
Project will obtain that kind of material — blood samples for direct storage, hair 
roots, and cells dislodged by gentle scraping inside the subject's mouth — not only 
from the 25 individuals whose transformed cells will be stored, but also from 100 
or more subjects in the sampled population or its immediate neighbors. 

Methods of amplifying the limited amounts of DNA thus obtained (that is, aug- 
menting the number of DNA copies) will also be developed and tested, but with our 
present knowledge, transformed cell lines offer the most satisfactory method of pres- 
ervation. 

Question 1.3. What is the best method for storing and assuring the continued 
quality of these blood samples? 

Answer. The most widespread and reliable method of transformation of white 
blood cells for the purpose of generating indefinite amounts of DNA is the treatment 
of B lymphocytes (a special type of white blood cells) with Epstein-Barr virus. Cur- 
rent investigations of genetic diseases use this procedure, and a repository of trans- 
formed cells (where we plan to house our collection) has been established for this 
purpose at Camden, New Jersey, by NIH-GMS. After preliminary cell multiplica- 
tion, B lymphocytes are stored in liquid nitrogen, and samples are taken when nec- 
essary for further multiplications. A very small fraction of DNA, involved in making 
antibodies, apparently is altered in these cells. For this reason it may also be impor- 
tant to store, without transformation, other cells from blood or tissues in which this 
part of the DNA is unchanged. 

Question 1.4. Immortal cell lines will require perpetual upkeep. What would be 
the long-term costs associated with this Project? 

Answer. A very large number of cell lines can be stored in relatively limited space, 
and it is inexpensive to replace the evaporating liquid nitrogen used to keep them 
at the right temperature. According to the Coriell Institute for Medical Research in 
Camden, after the initial project period, the costs for perpetual storage at May 1993 
prices would be about $4 per individual per year (including overhead), based on the 
amount of material we now think should be stored per individual. To maintain the 
full 10,000 cell lines that the Project contemplates — at least 25 individuals from 
each of 400 populations — would cost about $40,000 per year. This is equivalent to 
the amount that could be provided indefinitely by an endowment of $1 million, earn- 
ing a 4 percent return. That million dollars is only a few percent of the 5 year cost 
of the HGD Project as we see it today. 

Question 1.5. What kind of data bases will be necessary to manage the storage 
and retrieval of biological material? 

Answer. A data base will be needed to store the information on the origin of the 
various groups tested. This will include references to the relevant ethnographic and 
other anthropological information already available about the groups examined or 
gathered by the scientists involved in the expeditions. 

Another, much larger data base will contain all the data on DNA segments tested 
from the individuals of the survey. The need for such a data base is being consid- 
ered by the HGD Project, but any such data base should be compatible with the Ge- 
nome Data Base of the Human Genome Project, funded by the National Institutes 
of Health and the Department of Energy. 

Ideally, the same base pairs (the elementary units of DNA) should be examined 
on all the transformed samples from all the individuals, a highly desirable task but 
difficult to realize in its entirety. The size of the data base on DNA variation may 
be large, since it will be determined by the number of individuals tested times the 
number of base pairs tested on average per individual. The actual number of base 
pairs examined per individual may be considerably increased by technological devel- 
opments likely to take place in the next two or three years thanks to the Human 
Genome Project. The new technologies are almost certainly applicable very directly 
and in a highly efficient way to the HGD Project. It is possible that when the collec- 
tion of population samples has been completed, the total amount of information in 
the data base on human diversity might be of a size not far from that of the human 
genome itself, about 3 billion base pairs. 

Question 1.6. What minimum set of genetic markers should be analyzed for all 
samples? In what priority will samples be analyzed once a common set of markers 
will be established? 



47 

Answer. We don't have a precise answer yet, but in general, for reconstructing 
history, it is best to evaluate several hundred variable genetic sites. The experience 
accumulated so far shows that evaluating a large number of sites greatly enriches 
the analyses that are possible and consequently our understanding of human diver- 
sity. The great advantage of cell lines is that one can always return to them for 
more information. 

The analysis of variation can be carried out for single base pairs (the units torm- 
ing DNA), or for whole segments of DNA made of hundreds or thousands of base 
pairs. The latter approach is especially productive for those segments of DNA that 
are particularly variable. We already know some of these, and know some rules 
about where and why to expect more or less genomic variation, but more must be 
learned in order to accomplish a rational selection of the most appropriate DNA seg- 
ments. These segments should be a representative sample of the whole genome. 

Individuals and markers will be analyzed with priorities dictated by the amount 
of information they can provide. 

Question 1.7. Will 25 samples from each population be sufficient to gain important 
information about medical genetics? 

Answer. At the second workshop, we decided that collection of samples from 25 
individuals per population was the best compromise between the need for more pop- 
ulations and the desire to have more individuals per population Although this is 
adequate for most questions currently anticipated, it is not sufficient for investigat- 
ing all questions, especially those that focus on within-population variation at a spe- 
cific gene. This issue is being addressed in four ways: (1) the collection and storage 
of DNA of additional individuals from most or all of the populations, (2) the use of 
independently existing collections of stored cells and DNA, whether transformed or 
not, which may be donated to the HGD Project, (3) research work on establishing 
libraries of amplified DNA from non-renewable samples; and (4) establishing larger 
numbers of cell lines from a selected subset of populations. Items one and three 
were addressed briefly in the answer to Question 1.2. These additional resources 
will allow selected studies, and especially those of greatest medical relevance, to be 
carried out on a much larger sample from a number of populations. 

Question 2.1. Should any benefits of the research accrue to the research subjects? 

Answer. The donors of the blood and other DNA samples will benefit from their 
participation in the HGD Project in several ways. First, the Project may lead to im- 
proved information about medical problems afflicting the donor populations. Second, 
the Project would like to require that the developers of any commercial products cre- 
ated from the Project's samples pay royalties to a fund to be used to benefit the par- 
ticipating populations. Third, the Project intends to transfer biological technology to 
other parts of the world, thus providing some scientific and economic development 
in some of the countries from which samples are taken. Fourth, for many small and 
threatened populations, participation in the HGD Project should increase the gen- 
eral public knowledge of their existence and the dangers they face. This improved 
visibility may indirectly help protect them from a variety of outside pressures. 

Finally, in many cases the Project may be able to offer more immediate and tan- 
gible benefits to the populations through the provision of some immediate medical 
care. In Dr. Cavalli-Sforza's work with African pygmy populations, for example, he 
learned that 3 to 4 percent of the residents in camps he visited were afflicted with 
yaws, a destructive skin disease. He arranged, with assistance from drug firms, to 
bring them penicillin, which treats that disease very effectively. The kind of medical 
care that could be offered will necessarily vary with the circumstances, but the 
Project will encourage that kind of humanitarian return to the populations that are 
sampled. 

Question 2.2. What are the risks, particularly social risks such stigmatization, to 
research subjects who participate or decline to participate? 

Answer. The risks will necessarily vary from culture to culture, which is one of 
many reasons that the Project intends to sample only populations for which anthro- 
pologists or others have established a good understanding of the culture. Working 
with the experts in the culture, we will strive to arrange the donations so that no 
one would be harmed by his or her decision about participating. In fact, though, this 
kind of research has been done many times, and the researchers involved believe 
that this particular threat is extremely unlikely. Drawing blood is not a novel proce- 
dure for research in isolated populations. In almost all such populations, some peo- 
ple are willing to donate blood and others are not. Neither decision would normally 
put a person into a tiny and threatened minority. 



48 

Question 2.3. What limits are necessary to assure the confidentiality of the sam- 
ples collected? 

Answer. The identities of the individuals from whom samples are collected will 
not be publicly available, nor will the samples stored at the repository be identifi- 
able by individual names. We foresee no difficulty in protecting the subject's privacy 
or in following all applicable Federal law on confidentiality. 

Question 2.4. The issue of informed consent raises its own questions: What con- 
stitutes meaningful informed consent in non-Western cultures? Do notions of in- 
formed consent have any true relevance to some of the populations sampled? 

Question 2.5. How will the Human Genome Diversity Project comply with the 
"Federal Policy for the Protection of Human Subjects" (10 CFR Part 745)? What dif- 
ficulties might the project encounter subscribing to the human subject protection 
regulation? 

Answer. We believe it is most useful to answer these two questions together. 
There is a fascinating debate among researchers and ethicists about the meaning 
and propriety of "informed consent" in some cultures. Some have argued against the 
"ethical imperialism" of subjecting other cultures to American norms of disclosure 
and consent; others have urged that these are issues of universal human rights. The 
HGD Project does not need to take a position on this debate. Federal law requires 
informed consent, in fairly sharply defined terms; medical-anthropological research 
on isolated populations has proceeded successfully in the past subject to these legal 
requirements; and the HGD Project will comply fully with Federal law as well as 
the laws of the host countries. 

We do believe that the idea of informed consent is relevant for all human popu- 
lations. It embodies a respect for the individual that should be applied universally. 
The method of seeking informed consent necessarily will vary from culture to cul- 
ture, within the constraints of Federal law. How to describe the Project and its re- 
search in a way that has meaning to members of an individual population will vary. 
This again points up the vital role anthropologists and other experts on local popu- 
lations must play in the Project. 

The Federal regulations contain details that will be of limited value in some set- 
tings. For example, they might require the Project to provide written documents to 
populations that are entirely illiterate. We do see little difficulty in following them, 
as adapted for the circumstances with the agreement of the regulatory authorities. 

Further Information 

We appreciate this opportunity to supplement the record on both technical and 
ethical issues. On February 17, 1993, the Organizing Committee of the HGD Project 
held an all-day workshop on the ethical issues raised by the Project. We are attach- 
ing a copy of the summary and conclusions of that workshop to this testimony to 
provide the Committee with a resource for further exploration of these issues. In 
addition, we believe it would be useful to the Committee if we addressed briefly two 
other issues: the possible racist misuse of the Project's data and findings, and the 
implications of the HGD Project for public education in genetics. 

Racism is an ancient scourge of humanity. We would be deeply disturbed if the 
Project were to contribute to its survival or spread; in fact, some of those involved 
in this Project have been in the forefront of fights against earlier efforts to misuse 
genetics in racist ways. We believe that the Project is likely to undercut conven- 
tional notions of race and underscore the common bonds between all humans. 

For example, the Project will confirm and publicize that most genes are distrib- 
uted among human groups in ways very different from skin color or facial or body 
features. Those characteristics, which are largely though not exclusively driven by 
climate, tend to be visible, to be homogeneous within ethnic groups, and to be dis- 
tinctive from other ethnic groups — which is why they form the basis of traditional 
notions of race. Most genes, which are not directly related to the group's ancestral 
climate, vary tremendously within ethnic groups and only slightly between ethnic 
groups. The pygmy populations of Africa are quite different in some outwardly obvi- 
ous ways from most other human populations. But, over the entire genome, the ex- 
tent of diversity within any one Pygmy village is nearly as great as the diversity 
within the entire human species. The overall differences between the genes of those 
pygmies and the residents of nearly any other town or village in the world are likely 
to be small. Science already teaches us that traditional views of races and of "racial 
purity" do not make sense; the HGD Project will provide powerful confirmation for 
that conclusion. 

It is nonetheless possible that some findings or data from the HGD Project might 
be taken out of context in an effort to support racist attitudes. Although misuse of 
science can never be entirely prevented, the HGD Project takes this possibility very 



49 

seriously. We expect to deal with it in part by having "ready response teams" of sci- 
entists to respond to controversial claims based on the HGD Projects findings. 
These scientists would be ready immediately to speak with the media or the public 
to put such claims into their proper scientific perspective. No one would be censored 
or denied access to information, but the press and the public would get a balanced 
assessment of the claim. We know manv highly respected scientists from the diverse 
fields of anthropology, biology, and medicine who we believe would be happy to play 
such a role We believe that such an expert and balanced assessment of any con- 
troversial findings based on the HGD Project's work will cut against racist interpre- 
tations of genetic diversity, not in favor of it. 

Whatever the true probability of racist misuse of the HGD s Projects data or find- 
ings concerns about such misuse are both real and legitimate. We intend to reach 
out to Americans with the greatest reasons for concern— notably Americans from 
ethnic groups who have traditionally faced racial discrimination— and, thf "/" 
meetings or workshops, to engage in a process of mutual education. We would edu- 
cate them about the HGD Project and its likely findings; they would educate us 
about the kinds of misuse that might be expected and the grounds for their con- 

* This leads to the broader issue of public education. Public education is both part 
of the ethical agenda for the HGD Project and a benefit on its own. Better public 
understanding of the facts of human genetic diversity will, we are confident, dimin- 
ish the possibilities of racist misuse of the data. We expect to carry out such an edu- 
cational campaign. 

At the same time, the HGD Project provides a unique opportunity to expand pub- 
lic understanding of genetics. We have all noted the strong interest in this project 
from non-scientists, from all walks of life. Some are interested in historical ques- 
tions, some in human evolution, some in their personal family histories. Many of 
the people who find the HGD Project fascinating have not been as captured by the 
Human Genome Project. The HGD Project ties into many Americans' interests and 
imaginations at a more concrete level than mapping and sequencing ever could. The 
genetics revolution is one of the most (if not the most) important scientific advances 
of our time. The HGD Project provides a special way to interest more of the public 
in that revolution and, as a result, educate them about it. 



50 



April 13, 1993 

To: Participants in the Human Genome Diversity Workshop 3(B) on Ethical 

and Human-Rights Issues 

Non-Participants Who Expressed Interest 

Members of the Human Genome Diversity Corprnittee 
From: Henry T. Greely, Workshop Chair / 

Subjects: Summary of the Workshop Proc eed i ngs' "), 

My Recommendations to the Human Genome-BiveisiJy Committee for 

Structuring the Project's Ethics Component 

Attached you will find two documents that have come out of Workshop 3(B) of 
the Human Genome Diversity Project, on Ethical and Human-Rights Issues, held on 
February 17, 1993 at the National Institutes of Health at Bethesda, Maryland. As the 
organizer and moderator of that Workshop, I am sending these documents to all those 
who participated in the discussions, to those who could not participate but expressed 
substantial interest in the Workshop, and to all members of the Human Genome 
Diversity Project Committee, whether or not they attended the Workshop. 

The first, and longest, document is the summary of the February 17 workshop. 
The summary is lengthy and is based largely on tape recordings of the more than five 
hours of discussion. I have tried to set out, in some detail, the discussions that took 
place at that meeting, even though the length of the summary probably decreases its 
audience. The "Conclusions" section near the front of the document can be used as 
an executive summary. 

The second document includes my own recommendations to the Human 
Genome Diversity Committee on how to structure an ethics component for the Project. 
Although those recommendations were certainly greatly informed and aided by the 
Workshop, they should in no way be viewed as reflecting the consensus of the 
participants. 

I want to thank all of you who reviewed a draft of the summary. Particular 
thanks go to Dr. Irene Eckstrand, whose notes provided an invaluable supplement to 
the tape, and to Ms. Jean Doble, who along with providing logistical support at 
Stanford for the Human Genome Diversity Project, also offered her skills as a copy- 
editor. Apart from corrections of my numerous mistakes in transcription, there were two 
areas of significant change. First, conclusions number 1 and 1 1 were toned down in 
deference to a comment from Dr. Ellis that they seemed to prejudge the issue that he 
thought needed exploration. I believe I accurately captured the view of the majority of 
the people who participated, but I was willing to soften the comments in the interests of 
consensus. Second, Dr. Cavalli-Sforza has expanded his comments from the third 
session, which fell, in large part, into the gap of our tape recordings. 

The funding, speed, and immediate future of the Human Genome Diversity 
Project remains in some question, but I have no doubt that this work will be done. I 
believe that the Workshop made a very valuable contribution in exploring at least a 
few of the ethical and human-rights questions to which this kind of research will 



51 



inevitably give birth. And it was fun. I want to extend sincere thanks (on both counts) 
to all those who took part. 

If you have any questions or comments, you can reach me at (415) 723-2517 
(office telephone), (415) 725-0253 (office fax), or henry.greely@forsythe.stanford.edu 
(e mail). 



52 



Human Genome Diversity Project 

Summary of Planning Workshop 3(B): 

Ethical and Human Rights Implications 

Table of Contents 



Introduction 1 

Conclusions 1 

Workshop Summary 3 

First Roundtable -- Problems of Collection 3 

Dr. Joan Porter 3 

Dr. Kenneth Weiss 5 

Dr. Gary Ellis 7 

Dr. Rachelle Hollander 8 

Discussion 9 

Second Roundtable -- Problems of Commercialization 1 2 

Dr. Val Giddings 1 2 

Dr. Walter Reid 1 3 

Discussion 14 

Third Roundtable -- Problems of Misuse 1 7 

Dr. Diane Paul 1 8 

Dr. William Schneider 19 

Dr. Eric Juengst 21 

Dr. Luca Cavalli-Sforza 22 

Discussion 23 

Dr. Robert Murray 25 

Discussion 26 

Closing Discussion 29 

Appendix A -- List of Participants and Attendees (not included in draft) 

Appendix B -- Schedule, List of Possible Issues, and Identification of 

Participants (not included in draft) 



53 



Human Genome Diversity Project 

Summary of Planning Workshop 3(B): 

Ethical and HUMAN-RIGHTS Implications 



The third planning workshop of the Human Genome Diversity Project was 
held on the campus of the U.S. National Institutes of Health in Bethesda, 
Maryland, from February 16 through February 18, 1993. The second day of the 
workshop was devoted to an exploration of the ethical and human-rights 
implications of the Project. This open meeting centered on three roundtables, 
involving 12 invited participants, and the resulting discussions among all those 
present. Attendees and their affiliations are listed in the attached Appendix A. 
The discussion was guided by a schedule and list of possible issues, distributed 
to all present and attached as Appendix B. The meeting was organized and 
chaired by Professor Henry T. Greely, the principal author of this summary. 

This is a relatively complete, and thus lengthy, summary of the comments 
at the meeting. The beginning of the summary sets out as conclusions some 
issues on which there appeared to be widespread agreement, but those 
conclusions are not intended to serve as a set of detailed recommendations. The 
meeting organizer is distributing his recommendations in a separate 
memorandum; recommendations from others who attended the meeting are 
welcome and will be distributed by the meeting organizer to the participants and 
to the Project committee. 

Conclusions 

These 1 1 conclusions represent the views of most, if not all, of the 
individuals invited to participate in the meeting. These are the minimum 
conclusions to be drawn from the workshop and should not be viewed as 
precluding any participants from setting forth additional views. 

1 . The ethical concerns raised by this Project are both real and significant. 
Although no participant stated that those concerns are so serious that the Project 
should not go forward, the participants agree that careful attention must be paid 
in designing and executing the Project in order to minimize the risks of harm. 

2. Consideration of ethical issues needs to be integrated into the Project's 
decisionmaking, both in the planning stages and, on a continuing basis, during 
the life of the Project. 

3. The Project should be designed and executed with help from the 
populations to be sampled as far as is feasible, although the participants realize 
that there will often be enormous logistical barriers to such assistance. 

4. If any funding is obtained from federal agencies, American laws and 
policies concerning informed consent must be followed, but applying it in a 
manner that provides useful information to the populations to be sampled will 
sometimes prove difficult. No one method of providing informed consent will be 



54 



appropriate for every population. This kind of sampling has been done in the 
past in projects financed by federal agencies, so it seems likely that these 
difficulties can be surmounted. The Project should collect samples of informed- 
consent protocols for previously approved research. It may want to create 
several model protocols or to review itself the informed-consent protocols of 
researchers who seek to collect samples for it. The structure for central review, 
in any, of informed-consent protocols requires thought. 

5. The Project should consider beginning its sampling with populations that 
raise the fewest ethical and political problems. It should give special 
consideration to beginning with populations in countries that sponsor the Project. 
Experience with those populations, and a record of success in dealing with them, 
may be very helpful in sampling more vulnerable groups. 

6. It is not clear whether any governments of populations to be sampled will 
seek payments in return for the collection of DNA samples within their borders. 
The Project should consider what approach it would take to such requests. 
Because of the many sensitive issues involved in patenting genes, human or 
otherwise, the Project may want to agree that no genes may be patented using 
as a basis for the patent any work done on samples collected through the Project. 
It may also want to agree that populations or countries will receive some form of 
payment in the unlooked for event that samples collected for the Project lead to 
products of commercial value. The form of such payments requires further 
thought. 

7. Some people will almost certainly attempt to misuse the Project's data and 
findings in support of racist or nationalist ends or what Dr. Juengst has termed 
"demic discrimination." Whether that misuse would have any significant 
consequences is unclear, but the participants believe the Project has a duty to try 
to minimize the effects of such misuse. 

8. A program of public education would probably be a useful, and perhaps an 
essential, element in efforts to limit the misuse of Project data and findings. 

9. As part of such an education and information program, it is important that 
the Project define itself, its goals, and its limitations to the public, rather than 
allow it to be defined by others. Examination of past uses and misuses of 
scientific attempts at human differentiation may be a useful part of this effort. 

10. The Project should ensure that it is informed about the uses to which its 
samples and data are being put and the conclusions that are being drawn from 
them. It may want to be able to respond quickly to published work or press 
inquiries in order to ensure that claims made on the basis of the Project's work 
are put into their proper scientific context. 

11. There is no reason to believe that the ethical concerns raised by this 
Project are insurmountable. Most of the participants believe that, with 
appropriate safeguards, the Project should proceed. The Project should, 
however, evaluate throughout its life the ethical consequences of its work. If 



55 



unexpectedly strong and negative effects appear, the Project should be willing, if 
necessary, to bring itself to an early end. The Project should provide data that 
may be invaluable in answering important questions in a wide variety of fields, 
including genetics, anthropology, history, linguistics, and others that cannot yet 
be guessed. The value of this research and the urgency caused by the 
continuing disappearance of isolated human populations makes the ethical 
concerns all the more important. If the Project does not proceed carefully and 
properly, it could spoil the last good opportunity to obtain some of this data. 

Workshop Summary 

This workshop session convened at 9:30 a.m., February 17. Prof. Greely 
welcomed those in attendance, introduced the roundtable participants and the 
present members of the Human Genome Diversity Project committee, and made 
a variety of administrative announcements. He laid out his goal for the meeting -- 
not the resolution of many, or perhaps any, of the ethical and human-rights 
questions raised by the Project, but instead a narrowing and focusing of the 
issues involved. Dr. Marcus Feldman, a population biologist at Stanford and a 
member of the Human Genome Diversity Committee, then briefly explained the 
Project and described the planning workshops held thus far. 

First Roundtable Discussion - Collection Issues 

The first roundtable discussion covered the issues involved in collecting 
blood, DNA samples, and information from populations of interest to the Project. 
Prof. Greely noted some of those issues briefly, then turned the meeting over to 
the four speakers on that issue: Dr. Joan Porter, Dr. Kenneth Weiss, Dr. 
Rachelle Hollander, and Dr. Gary Ellis. 

Dr. Joan Porter 

• Dr. Porter, senior analyst with the Office of Protection from Research 
Risks (OPRR) of the Department of Health and Human Services (HHS). The 
OPRR implements HHS regulations that protect human subjects. She began by 
reviewing the historical development of ethical strictures on human 
experimentation, starting with the Nuremberg Code and the Declaration of 
Helsinki and drawing special attention to the Council for International 
Organizations for Medical Sciences (CIOMS), which also provides guidance on 
ethical issues. 

In the United States, federal regulatory law is based on the Belmont 
Report, prepared by the National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research in 1979. That Report focuses 
on three principles: 

Respect for Persons : 

This principle requires researchers to seek informed consent from subjects 

and to provide special protections for people with diminished ability to 

consent. 



56 



Beneficence , which includes the principle of non-maleficence: 
Non-maleficence means doing no harm; beneficence means doing good. 
This principle is realized largely through careful prospective and ongoing 
risk/benefits analysis by an independent committee. 

Justice : 

This principle means many things, including treating people fairly. 

Equitable selection of subjects is one way to help ensure justice. 

Most of the principles focus on individuals, but justice also concerns 
populations. The Project lends itself to a "macro-ethical" framework, focusing on 
communities rather than only on individuals. In considering macro-ethical 
issues, she has found particularly useful the International Guidelines for the 
Ethical Review of Epidemiological Studies, prepared by CIOMS in 1991, although 
there are some differences between those guidelines and American law, 
particularly on informed consent. She believes the Project raises several 
particularly interesting macro-ethical questions: 

Will the studies be able to maximize benefits to the community by 
communicating the results? 

Will there be a way to minimize harm by avoiding stigmatization or 
prejudice or loss of self-esteem or economic loss? 

Can harmful publicity be avoided? 

Can some kind of confidentiality be retained for groups? 

Dr. Porter then set out ten other areas of concern that she believed this 
group and the Project's organizers must address. 

1 . What are the real risks and benefits to the individuals and communities? 
Physical risks are probably minimal, but it is important to anticipate any 
social risks. 

2. Will genetic information be individually identified? 

3. Will the sampling process lead to any information of use to the individuals 
sampled? For example, if a subject's blood had a genetic marker for 
breast cancer, could (and should) any useful information be conveyed to 
that individual? What would happen if everyone in the sample had the 
marker? 

4. Will information about disease susceptibility have any possibly subtle 
effects on employment, immigration, or access to health care for the 
subjects? 

5. Will samples be taken from families and, if so, what concerns are there 
about pressures to participate, recruitment issues, and problems of 
confidentiality that have been recognized in large pedigree studies? 

6. Will any inferences be made about the relationships between non-human 
primates and certain groups? 

7. Are the groups of most interest to the Project among those most 



57 



disenfranchised in their societies and, if so, what are the implications of 
this status? Who can give permission for such groups? 

8. Will DNA from non-living persons be collected? How can community 
sensitivities about that kind of collection be taken into consideration? 

9. What kind of local independent assessment is important? If there are 200 
sample areas, will there be 200 institutional review boards (IRBs)? HHS 
generally prefers local IRBs but perhaps there is an equally effective and 
more efficient method to do this. 

10. How can we ensure appropriate recognition of collaborators, particularly 
those from other countries? 

The Project presents an unprecedented opportunity to advance some 
areas of human knowledge, making it crucial that we think through the ethical and 
legal issues carefully. 

Dr. Kenneth Weiss 

Dr. Weiss is a professor of anthropology at Pennsylvania State University 
and a member of the Human Genome Diversity Committee. He started by noting 
that many of the populations to be sampled will be in urban areas. For them, 
many of the standard answers to ethical issues will apply. Dr. Weiss focused his 
presentation on the special problems of sampling populations that are living in 
isolated circumstances and under relatively traditional conditions. He stressed 
that, because of differing conditions, no one approach would work for every 
population. 

The first challenge will be to explain the Project's goal to these 
populations. Explaining that the Project wants blood isn't difficult (though it may 
lead to rejection), but explaining the goals can be harder. For example, he noted 
that describing one of the goals of the research as discovering information about 
the origin of a population would be meaningless, or perhaps insulting, to many 
populations that have their own deeply held beliefs about their origins. Such an 
explanation could do cultural harm as well as jeopardize the efforts to get 
permission. In general, explanations must to be made by people who are very 
familiar with the populations, whether they call themselves anthropologists or not. 

All communications must occur in the local language and each must to be 
tested to make sure it is correctly understood. Although that requirement is not 
very different from how any kind of epidemiological survey is done, it is more 
challenging in uncommon languages. 

Whether the identity of a studied population should be publicly revealed 
through the research is an interesting point. Anthropologists have long been 
divided over the degree to which they should identify specific populations with 
which they work. This would have to be done differently in different contexts. 
Identifying isolated communities can sometimes harm those communities and 
sometimes work to their benefit. This is a real issue, although one without a 
blanket answer. 



58 



The disease questions are interesting, although breast cancer is a bad 
example for most of these populations. Something like HIV infection is more 
sensitive because it might have political ramifications. In some places, disclosure 
of infection could bring help, and in other places, it could bring harmful attention. 
Someone familiar with the area and the population needs to decide how to deal 
with samples that show signs of disease before any collections are authorized. 
No one standard can apply everywhere, but wherever possible, people with 
current disease should be referred to the national health systems when possible. 
In many countries, referrals to a national health-care system can make a 
difference in the health care provided to individual subjects, which may lead to at 
least a temporary quid pro quo. For a few populations, there will be no health- 
care system to which they can be referred. 

In some populations, payments are required for the research, either to 
local leaders or to individuals in the studied group. In some of those populations, 
payments will have to be made to a local leader because paying individuals 
directly rather than the group leader would disrupt the social system. A person 
who has experience with that group must decide these issues. 

Coercion means different things in different situations. Bravado or lack of 
bravado, for example, may have a major effect on who volunteers. If coercion 
happens, it will be from within the population. Sometimes a person who works 
within the group will have to be persuasive in order to get consent. In many 
populations, getting a signed consent form will be impossible. People will not 
sign any form, no matter what it says, because of their intense suspicion that any 
written form will be used against them. 

"Immortalization" can be a very sensitive term and should be avoided 
when talking about the intended creation of cell lines. (Someone suggested 
using "transformation," the standard European practice.) Whether to tell people 
what you intend to do, as a technical matter, is a difficult question. Translating 
the concepts will be very hard. 

As to anonymous samples from dead people, the National Graves 
Protection and Repatriation Act in the United States provides rules for the return 
of skeletal remains. If you can identify an existing successor group to which the 
remains are related, that group's permission is necessary; if you cannot identify 
an existing group to which the remains are related, he believes they may be used 
without permission. 

The use of fetal and placental tissue will, of course, be governed by local 
rules and morals. There is no blanket answer to whether you should be able to 
take samples from people who appear at isolated hospitals outside their home. 

Getting permission is complicated and, again, differs in different areas. In 
working with Native American tribes in the United States, for example, you get 
permission from the tribal group and go around to the populations with 
representatives of that group. In some parts of the world, approval must also be 
sought from a government from outside the population to be studied. In many of 



59 



these populations, anthropologists or linguists are already working with the 
population and can facilitate obtaining permission. Before any collection activity 
would be funded, its leaders would have to document to the satisfaction of a 
reviewing group that they understand the permission process in that region and 
are complying with it. How the review group could check on that information is 
not clear, but it could not demand an identical process for every population. The 
Project must always work with people who are familiar with and trusted by the 
groups to be sampled. 

Dr. Gary Ellis 

Dr. Ellis has recently become director of the Office of Protection from 
Research Risk. His office regularly hears from researchers who say that the 
rules don't fit into their research. His reaction is "let's find a way." Informed 
consent is a process, not just a form, with the prospective research subject's 
ability to make a voluntary decision as the key requirement. The procedures 
should be designed to educate the subjects in language and terms they can 
understand. The document should be a teaching tool, not a legal document. Lay 
language, understandable to the potential subjects, must be used even though 
this is difficult in other cultures. It is important to have a written document so the 
subject can refer to it in the future. 

U.S. federal government regulations lay out eight elements of informed 
consent. 

1 . The informed consent must state that the study involves research, must 
explain the purposes of the research and the expected duration of the 
subject's participation, and must describe the procedures to be followed 
with a special description of any procedures to be followed that are 
experimental. 

2. The informed consent must describe any reasonably foreseeable risks or 
discomforts to the subject. 

3. The informed consent must describe any reasonably foreseeable benefits 
to the subject or others. 

4. The informed consent must disclose any appropriate alternative 
procedures or courses of treatment that may be advantageous to the 
subject. 

5. The informed consent must state the extent to which confidentia.ity of 
records identifying the subject will be maintained. If the Project found that 
someone had a disease and went back and referred them for treatment, 
obviously the samples would have to be linked to the donors, which may 
not be the best approach. 

6. In research involving no more than minimal risk, the informed consent 
must explain whether any compensation or medical treatments would be 
available if injury occurs, what the compensation or medical treatments 
would be, and where further information about those matters can be 
obtained. 

7. The informed consent must tell a prospective subject whom to contact for 
answers to questions concerning the research, the research subject's 
rights, and whom to contact about any research-related injuries. These 



60 



questions ordinarily cannot all be answered by the same person for 
reasons of limited knowledge or conflict of interest. 
8. The informed consent must state that participation is voluntary and can be 
declined without any effect on eligibility to benefits and that participation 
can be discontinued at any time without any penalty or loss of benefits to 
which the subject is otherwise entitled. The Project needs to consider 
what discontinuation means in a context where there will be ongoing cell 
lines and databases. 

Dr. Rachelle Hollander 

Dr. Hollander is Director of the Ethics and Values Studies program of the 
National Science Foundation. She began by noting that the rhetoric of science 
romanticizes or mythologizes the science. Research subjects, on the other hand, 
tend to de-mythologize science. Both the public and geneticists need to be 
educated about the Project. Genetics has a mixed record in its effects on people. 
The urgency of this Project needs to be moderated by the recognition that it is 
important to go slowly enough for the public and the scientists to understand the 
consequences of the science. 

The Human Genome Diversity Project was mentioned at the AAAS 
meeting and was the subject of some misunderstanding. For example, some 
wondered why we should study diversity when geneticists can create diversity. 
Others wondered why people were concerned about preserving DNA but not 
ways of life. There are concerns about evolution within humans because the 
public and scientists often equate "early" to "primitive" to "less valued." 

The need for the involvement and approval of affected communities, from 
local level to the nation-state, is crucial. What counts as "owning", or "having 
access," or "benefit" will differ in different cultures. Does this Project involve 
questions of common human heritage? Will there be questions of ownership or 
disputes over property rights? How will that be managed? Property rights will 
make a difference in obtaining informed consent because it affects what you are 
seeking consent to do. Reciprocity is fundamental and so the Project will have to 
think about the interactions between the researchers, the sponsoring 
governments, the populations, and the nation-states that include the populations. 

The process of answering these questions must empower individuals from 
affected populations. They should be involved in developing the Project as well 
as in allowing access to populations. Informed consent as a mark of respect is 
very important; respect is an idea shared by many cultures, but sometimes 
expressed in different ways. Does this consent make sense in terms of the 
community or person giving the consent? Is there reciprocity? What do they 
think is important? That kind of evaluation is important and it is important that it 
be ongoing, throughout the Project. 

The group might want to devise ethical guidelines for the research, but do 
so with the participation of the groups involved. This will also lead to the 
development of ideas about what community payback might be appropriate. The 
process should also incorporate ongoing evaluation of those ethical guidelines. 



61 



The document summarizing the second workshop ends by saying that all 
materials and data not confidential should be available to all. What that means 
requires considerable thought. 

Discussion 

Prof. Greely noted the tension between centralized review for western 
standards and federal rules, on the one hand, and making allowances for local 
conditions and cultures, on the other. Devising a process that does both is not a 
trivial issue. 

Dr. Paul said it is useful to note what we know about informed consent in 
American medicine. We know a lot about how it works, and it doesn't work as "a 
teaching tool" to help patients learn. For American researchers and doctors, the 
phrase is "getting consent" and it is viewed as a defense against malpractice 
suits. Nancy Press's recent research on maternal serum alpha fetal protein 
screening showed that most of the women signing the consent form either didn't 
know that they had had the test or thought the test was some form of therapy for 
the fetus. The true significance of informed consent differs from the ideal even in 
the United States. (Prof. Greely noted that "consent" has become a different 
kind of verb in American medicine - rather than patients consenting to treatment, 
doctors "consent" the patients.) 

Dr. Giddings seconded those remarks. He thinks the Project runs a risk 
of getting into a political morass. The Project will inevitably have to deal with 
local political structures, and many people in those structures will not believe 
whatever the Project says because its representatives will be from the developed 
world. He hesitates to suggest getting involved with the United Nations 
bureaucracy, but it might be a good idea. The political problems are so great that 
the Project must either keep a very low profile or seek political cover, and a low 
profile is impossible. The Project might want to get involved with the World 
Health Organization. It might also want to divide the populations of interest into 
low, medium, and high political risk. It could sample the low risk populations first, 
as well as populations from the sponsoring nations first. Pursuing the Project 
poorly might poison the well forever for future scientists. Lots of people will be 
very suspicious about the Project. Even though those suspicions may be 
inappropriate, you have to deal with them. 

Dr. Siniscalco pointed out that he has a lot of experience on these issues 
from his work with the European Commission. The study of human genome 
diversity has been done for a long time -- it constitutes the core of human 
genetics. Various groups have been doing this kind of research and have been 
interacting with local governments as well as funding organizations. The main 
effort should be to advertise the importance of the Project. He suggests 
something like the DNA Learning Center at Cold Spring Harbor in an effort to 
educate the public. He exhibited a copy of the Cold Spring Harbor exhibit in a 
museum in Sardinia and found that the public was extremely interested. He 
believes the Project also needs to emphasize the crucial importance of 
environment in its interaction with genes. The Project should not need to keep 
information about individual samples that identifies their donors, because 



62 



individuals will need to be tested only if a medically important gene is found. 
There are rules and regulations for this kind of research, but the Project should 
focus on inventing a system to uphold those standards. We have an enormous 
opportunity; but we need to explain the Project to people in order to gain their 
trust. 

Dr. Reid pointed out that although this kind of work has been going on, this 
Project will face new obstacles. One reason is the scale of the Project. It will 
attract attention from people who wouldn't otherwise know that this kind of 
research is going on. The international political context will also be disturbing. 
The combination of the Rio discussions and the ethical dimensions raised by 
dealing with human genes will attract an enormous amount of attention. 
Education about the motivations for the work won't be enough; it comes down to 
a question of creating a process that makes this workable. He shares some of 
Dr. Giddings's skepticism about the United Nations but believes that it deserves a 
very hard look because of the certifying role a U.N. connection might play. He 
also thinks it would be very valuable to involve the subjects of the research in the 
planning, although he recognizes the tremendous logistical problems. Finally, it 
will require tremendous anthropological expertise in the populations to be 
sampled; maybe that should be factored into the considerations for choosing 
populations. (Prof. Greely pointed out that the existence of such expertise had 
been one of the considerations the second workshop used for suggesting 
populations to be studied.) 

Dr. Juengst agreed that the Project will have a high visibility, which will 
change the dynamics. That has happened with the Human Genome Project; 
mapping and sequencing studies had been going on for a long time, but a 
coordinated Project with a capitalized name becomes a lightning rod. As a result, 
many of the rules for various studies are being reinvented, at least to provide 
coordination within the Genome Project. It may be the case that all that is 
needed here is to codify existing rules for pursuing this kind of work. 

Dr. Cavalli-Sforza stated that we may be making the problems seem more 
difficult than they actually are. He has collected samples from some of the most 
isolated and difficult locations in the world. You must have the permission of the 
local authorities, or they may put you in jail, and you must have the permission of 
the local people, or they won't participate. The permission issues are therefore 
self-policing. The important issue is the information. Right now, we cannot name 
any immediate benefits, except possibly with respect to vaccination, which is 
itself controversial among many people. It is very difficult to explain the science. 
A traveling Cold Spring Harbor show is a good idea and may work in the cities, 
but it won't work in the villages where most of the sampling will be done. It may 
be very difficult to acquire a consent that is as informed as the American 
regulations seek, but we should go as far as we can. 

He has been trying to get the involvement of UNESCO. UNESCO is 
preferable to WHO, because the Project has no immediate medical purpose. He 
had a conversation with the Director General of UNESCO, who was very 



10 



63 



supportive. He agreed with Dr. Weiss that it was impossible to have general 
rules; we need to stick to the general rule, "do no harm." 

Dr. Schneider was reminded of the fact that the largest samples of blood 
for blood grouping came from troops on the Salonika front during the First World 
War. Dr. Hirzfeld, who, with his wife, collected the blood, said in his memoirs that 
how he collected blood depended on the nationality of the troops. The British 
troops would do it if they were told it was "for science"; the African troops would 
do it if told that they could get out of military service; and the French troops would 
do it enthusiastically if told it would let them know with whom they could make 
love with impunity. Consent issues go back a long way; scientists are pragmatic 
and do what they have to do to get the material. He suggested that the proper 
model might not be medical studies, but traditional anthropological studies 
because this is not, basically, medical research. Are consent forms used by 
anthropologists? Another important question is what will be done with the drawn 
blood. Will this be used as a storehouse for future work, or just be analyzed 
once? If it is used for a long time, one can't be sure what the uses will be. 

Dr. Weiss said that anthropologists don't use forms, but they do get the 
permission of the groups they study. The Human Genome Diversity committee 
has known from the beginning that local government approval will be essential 
and has thought about technology transfer within that context. He thinks we are 
flattering ourselves to think that the Project will have a high profile. Most of the 
time, the permission is local, from government officials who want to know that you 
are there and that you are not going to stir up trouble. Anthropologists get 
approvals in most parts of the world without much trouble, although there are 
occasional, usually temporary, exclusions. Some groups like being studied. 
Groups are very different; confidentiality is meaningless in some contexts. In 
some groups, doing something in someone's house, away from the group's sight, 
would be seen as offensive to other members of the group. You more often have 
to include people you don't want rather than exclude people you do want. To the 
Committee, from the point of view of funding the Project, it is very important that 
the Project promises not to reveal individual's names to outsiders. 

Dr. Ellis asked who is sponsoring the Project; the response was that we 
don't know yet. The workshops are planning workshops to put together the 
framework for writing proposals. Prof. Greely pointed out that if the Project wants 
U.S. funding, the U.S. regulations will have to be followed for legal reasons, as 
well as for ethical concerns. He agreed with Dr. Weiss that the application of the 
principles would necessarily differ from culture to culture. He agreed with Dr. 
Siniscalco that this kind of work has been going on, so protocols have been 
approved. Finally, he agreed with Dr. Juengst that, perhaps, "codification" of 
protocols that have already been used would be sufficient to deal with these 
issues. 

Dr. Ellis added some political advice, saying that the Project should define 
itself to the public in simple terms first, before someone else does it. It would be 
a shame, for example, if someone said this Project was intended to find the 



11 



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genetic basis for violence around the world and the Washington Post reported 
that. 

Dr. Giddings said there is a substantial amount of evidence to indicate that 
this Project is being prosecuted by some guiding intelligence. There will be no 
way to go forward without a lot of local involvement -- there may be no feasible 
alternative to funding from something other than a multinational consortium. For 
political and financial success, this will have to involve multiple governments or 
international agencies. 

Dr. Bodmer pointed out that Europe is involved. The European 
Community has provided some funding and is interested in providing more. 
European populations are to be sampled as part of the Project, with at least some 
European funding. There is interest in making genetic diversity part of the next 
European funding framework for the biological sciences. 

Dr. Schneider asked for clarification about the boundaries of "Europe" for 
work funded by the European Community. Dr. Bodmer replied that the European 
side of the Project was able to act outside the boundaries of the European 
Community, including doing work in Eastern Europe and the former Soviet Union. 
Dr. Siniscalco noted that the European group is exploring the possibility of Soros 
Foundation grants for working in Eastern Europe and the former Soviet Union. 

Dr. Piazza asked whether it would change things if we collected 
mouthwash rather than blood. Prof. Greely said it would probably change only 
the details of the consent, but wouldn't make major changes in the process. 

Dr. Feldman noted that throughout the Committee's endeavors, it has had 
close contact with both China and Japan. The vice president of the Chinese 
Academy of Sciences was present yesterday and will be tomorrow. 

Second Roundtable Discussion •• Payment and Property Issues 

The second roundtable discussion explored issues concerning the 
possible commercial value of the Project's samples, cell lines, or findings. Prof. 
Greely explained that he had included these issues in the workshop because he 
believed the recent Biodiversity Treaty would lead some countries with 
populations of interest to the Project to seek royalties or other payment for 
sampling the genes of populations within their borders. He then turned the 
meeting over to the two speakers on that issue: Dr. Val Giddings and Dr. Walter 
Reid. (The third scheduled speaker, Dr. Jason Clay from Cultural Survival, Inc., 
was not able to attend because bad weather grounded his flights from Boston. 
Dr. Clay is receiving copies of this summary and other correspondence 
concerning the Workshop and has been invited to submit a statement of his 
views for distribution to the group.) 

Dr. Val Giddings 

Dr. Giddings, whose training was in human genetics, participated in the 
U.S. government's negotiating team for the Biodiversity Convention. He read 



12 



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excerpts from the Convention's provisions concerning technology transfer and 
payment. 

He said that the Convention and the negotiations from which it emerged 
will have important implications for this Project. It is a new era for genetic 
resources. The Food and Agriculture Organization's principle of "free access" to 
genetic resources is not going to survive. Movements of genetic resources 
across international boundaries in the future will be subject to a variety of 
constraints, particularly if there is any reasonable inference that the resources 
could result in commercial products. He urged that the Project must anticipate 
those constraints and build in some kind of agreement for royalty partitioning or 
some other provision for distribution of fair and reasonable benefits. Otherwise, it 
won't be able to get permission to take samples. 

Dr. Walter Reid 

Dr. Reid is associated with the World Resources Institute and has a 
special interest in issues of global biodiversity. At Rio, Dr. Reid participated with 
other organizations in developing a strategy for conserving biodiversity around 
the world. That process was not as polarized as the Convention negotiations, but 
it also reached the conclusion that the era of treating biodiversity as a common 
heritage or open access resource is over. Arguably, the distribution of benefits 
from the old regime was not equitable, and developing countries see 
opportunities to get more benefits in the future, through both financial 
arrangements and technology transfer. 

In the Convention negotiations, intellectual-property rights and technology 
transfer were most contentious. This Project will not have a profile as high as the 
Convention's, but he suspects that the Project could not go into countries to get 
permission for sampling without encountering officials who were familiar with the 
Convention. Those officials might draw on the Convention's terms to deal with 
the Project's request, particularly in countries that signed the Convention. 

He drew a parallel to the existing seed banks, which were collected under 
the common-heritage regime. For example, there is a bank of 60,00 or 70,000 
varieties of rice in the Philippines, with copies in the United States. The 
Convention negotiators decided they couldn't deal with the existing collections 
and so excluded that material collected in trust for humanity. How to deal with 
those materials remains a subject of discussion. Some seed banks are talking 
about patenting their materials to make them available; others prefer a situation 
whereby the seed banks only transfer material subject to a materials transfer 
agreement that includes a provision that no one seek a patent on the material. 

Because this Project seeks discoveries for all humanity and commercial 
profit is not its main concern, he suggested that the Project sign material-transfer 
agreements with the host country and with anyone who took samples from the 
Project. Those agreements should provide that no genes in the materials would 
be patented. Although such a ban on patents might not have much practical 
importance, the issue of patenting genes is politically very sensitive in many 
countries. A stipulation that no one would patent genes taken from cell lines from 



13 



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the Project, combined with an undertaking to share profits if the Project's cell 
lines led to products with commercial value, would be very useful. He argued 
that unless the Project made a preemptive strike on the patent issue, it would 
open a Pandora's box. 

Discussion 

After an inquiry from Prof. Greely, Drs. Giddings and Reid said that the 
Biodiversity Convention neither expressly includes nor expressly excludes 
coverage of human genetic resources. Dr. Giddings agreed with Dr. Reid on the 
importance of a preemptive position on this issue, though he would allow more 
scope for intellectual property protection for materials that had been improved in 
accordance with international common law or U.S. patent law. 

Prof. Greely, seeking clarification, posed a hypothetical question. If the 
Project discovered that an isolated population had a gene that protected it 
against an infectious disease and a researcher using the Project's cell lines 
isolated the gene, found the protein for which it coded, and patented not the gene 
but the protein as a basis for a drug, would Dr. Reid expect problems? Dr. Reid 
said that the major political concern in most countries was the actual patenting of 
the gene. Protection for the protein would be appropriate, although he thought it 
should come with some sort of return to the host country. Dr. Reid thought the 
discovery of a human gene that a commercial firm wanted to add to a crop's 
genome would be a much trickier issue, although one unlikely to arise. In such a 
case, the firm would want to patent the gene itself. It would be useful to the 
Project to say, from the beginning, that no patents will be sought for genes taken 
from the Project's samples. A firm interested in patenting the gene could always 
go back independently to the country where the gene was found and make 
whatever financial arrangements were appropriate, but that would not implicate 
the Project. 

Dr. Giddings said limiting a ban on patenting to the gene itself would 
eliminate many, if not all, of the problems he had seen with Dr. Reid's position. 
Even so, he believes Dr. Reid's proposition would meet with opposition from the 
governments of some developing countries. The developing countries often 
have a completely erroneous view of the process of product development and 
one that will often hurt innovation. Questions of intellectual-property rights should 
not be involved significantly in this Project. This Project is a research project, not 
intended to have commercial value, and should deal with these issues only to the 
extent necessary to avoid real political problems. 

Dr. Kenneth Weiss said the Committee wanted to make sure that anyone, 
anywhere in the world, can get access to the samples for research. He also 
pointed out that none of the property rights, or benefits, involved here are likely to 
get back to the villages. He argued that we aren't really talking about benefits to 
the people who would be sampled. Prof. Greely said he hoped they would 
discuss how to try to get the funds back down to the sampled population. Dr. 
Giddings said the Food and Agriculture Organization had been dealing with this 
at some length and found that there was no good solution. He believes that the 
Project would be better off avoiding this very tricky issue. 



14 



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Dr. Paul noted her disagreement with Dr. Giddings's view of intellectual 
property and the developing world and then asked for clarification of the positions 
of Drs. Giddings and Reid. Dr. Reid said that the issue of patenting genes may 
be relatively trivial as a practical matter, but that possibility would raise a lot of 
political concerns. Unlike Dr. Giddings, Dr. Reid thinks developing countries, 
such as India, might well accept his formulation. For one thing, it would allow 
them to continue to sidestep the tricky issue of the patentability of human genetic 
material. 

Dr. Schneider asked whether the Project could proceed by excluding any 
possible commercial use. Prof. Greely said it would be hard to exclude 
commercial use while keeping open access to the cell lines. And he added that 
the distinction between research use and the subsequent commercial use would 
be difficult. Dr. Schneider said perhaps you could prohibit the commercial use of 
the sample; it was pointed out that copying the materials would be easy. 

Dr. Siniscalco raised the possibility of having any royalties or profits 
derived from the Project going to an international body to be used for general 
human benefit. Prof. Greely replied that the question was really one of what host 
governments would accept. Dr. Feldman pointed out that if part of the funding 
came from U.S. government sources, researchers would have to sign a standard 
patent form. He was not sure what effects, if any, that form might have on 
obligations to the host countries. No one present knew the answer to that 
question, although Dr. Eckstrand pointed out that almost every bilateral 
agreement involving the NIH contains annexes dealing with the division of 
property rights in different countries. These generally reserve intellectual- 
property rights in different parts of the world to participants from different 
countries. 

Dr. Reid noted that one could have any royalties go to a UNESCO fund to 
be used to promote technology transfer to developing countries. UNESCO 
management would alleviate many political concerns; technology transfer was a 
major concern in the Biodiversity Convention negotiations. Prof. Greely noted 
that this still would not directly help the sampled populations, although Dr. Weiss 
pointed out that about three-quarters of the populations to be sampled would be 
groups that were integrated into their country's economy and culture. 

Dr. Reid said there had been a great increase in awareness among 
ethnopharmacologists of the need to help the communities involved in their 
research. There are not formal contracts, yet, but there has been a great 
increase in the benefits going back to the affected communities. The New York 
Botanical Gardens has been funding health centers and other benefits the 
populations want. This has been going on without the attention of national 
governments. 

Dr. Evans pointed out that the significance of a gene can only be seen 
from the entire samples; one cannot know that one population's allele is 
important without comparing it to the entire sample. The complexity of 



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compensating the populations from all over the world is daunting. She also 
pointed out that this Project should not be viewed in isolation, but as an offshoot, 
to some extent, of the Human Genome Project. In that Project, the thrust of the 
discussion is against patenting genes but in favor of patenting their useful 
applications. Commercial interests will come in at that stage. If the information is 
available to industrialists, you cannot stop them from trying to use it or to protect 
any valuable applications they make. She pointed out that patenting genes is 
different from patenting useful knowledge derived from them. 

Prof. Greely said he thought Dr. Evans's point on the importance of all 
populations was very important. He recalled a suggestion Dr. Eric Lander had 
made to him in a telephone conversation that any royalties should be viewed as a 
"mutual fund" for the benefit of all the sampled populations. This, he felt, plays 
back into the idea of UNESCO or another international organization as 
fundholderto promote the interests of indigenous peoples or, perhaps, those who 
contributed samples to the Project. 

Dr. Paul noted that the discussion was confusing two separate questions - 
who is the appropriate fundholder and what is generating the funds. There will be 
disagreements between proponents of intellectual-property rights and proponents 
of the Third World's interests. The Project will have to confront those broader 
issues and not just questions of the patenting regime. 

Prof. Greely urged that the Project needed a consistent approach to avoid 
having different arrangements with different countries. 

Dr. Siniscalco pointed out that patenting a gene, gained through one 
method, could be circumvented easily. Those who gain will be those who build 
the product most efficiently; another slightly different version of the gene could 
always be found for use. Prof. Greely argued that, even if the practical 
implications of intellectual-property rights in these genes were meaningless, it 
may be necessary for political reasons for the Project to have a position on this 
point. Dr. Giddings suggested that it might be easy for the Project to offer high 
royalties, because the Project would not, in fact, be conceding much of value. 

Several people disagreed over what legal or ethical entitlements might be 
owed to those people or populations who provided samples that led to 
commercial products. The Moore case in California was evidence that at least 
one donor thought he had property rights to his cells and that issue has been 
settled, as far as those present knew, only in California. Dr. Giddings urged that 
the Project need not answer all these issues before going forward; he supported 
Dr. Reid's general approach as a good way to deal with the issues. 

Prof. Greely noted that some ethicists felt that human genes, and humans, 
could not ethically be turned into market commodities. He did not know whether 
anyone at the workshop took that position but sought comment on it. Dr. Evans 
said it was very important and noted the different European laws on payment for 
blood donation. Prof. Greely noted American laws banning payment for most 
organs, and Dr. Evans said the same was true for many countries in Europe. 



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Dr. Evans noted that the European Project was considering seriously 
advertising for donors so that everyone who was sampled would have made an 
affirmative decision to come forward and participate in this Project. She 
recognized that this method could not be extended to every population, but 
thought it should be kept in mind. The information seeking participation could 
include language dealing with property issues. 

Dr. Weiss pointed out that this discussion fed back into informed consent. 
It would be very difficult to explain to people that their blood could be "sold" or, 
having explained it, to get their permission to take samples. Distributing the 
subjects' genetic material as a business would raise great concerns. Dr. 
Feldman pointed out that one goal was to have several cell banks, located in 
various regions. The laws of distribution of the cells are likely to differ in major 
ways among these countries; whatever the Project wants to do may be overriden 
by those local laws. 

Dr. Schneider noted that he personally would be much less likely to donate 
blood if he were told it would be used to make a profit. He then raised the 
question of whether any governments were very eager to participate in the 
Project and even wanted to do a more thorough study. Dr. Evans said that 
France had already done a province-by-province study of its populations and 
was, as a result, more eager to participate in the overall Project. 

Dr. Weiss noted that some countries might demand, as a short-term quid 
pro quo, laboratory facilities in return for giving permission to sample. 

The U.S. government is interested in looking at variation within its borders 
for forensic purposes. That raises concern among some groups. Dr. Cavalli- 
Sforza pointed out that the Project was not likely to have major value for forensic 
purposes because most of the populations it will sample are not heavily 
represented in the U.S. population. 

Dr. Bodmer noted that there had been a Japanese study of 128 different 
populations. The cell lines from that study were considered public domain, with 
no identification of individuals. There was no government involvement in this 
because the people who collected the data were from the countries where the 
sampled populations were located. 

Prof. Greely noted again his belief that the higher profile of the Project and 
the negotiation of the Biodiversity Convention would make past experience a 
poor guide to predicting host governments' demands in the future. 

Third Roundtable Discussion -- Racism and Other Possible Misuses of the 
Project's Data 

The third roundtable discussion concerned the possible misuse of the 
Project's samples or results. Prof. Greely started by saying that he thought the 
issues in this roundtable were the most important to be discussed today. 



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Although a variety of misuses is possible, Prof. Greely noted that, as an 
American familiar with America's historical problems, he considered white-black 
racism the greatest concern. He then turned the meeting over to the speakers on 
that issue: Dr. Diane Paul, Dr. William Schneider, Dr. Eric Juengst, Dr. Luca 
Cavalli-Sforza, and Dr. Robert Murray. (Dr. Murray was detained by an 
emergency and arrived late in the discussion of this issue.) 

Dr. Diane Paul 

Dr. Diane Paul directs the Program in Science, Technology, and Values at 
the University of Massachusetts at Boston and has studied the social history of 
genetics. She started by saying she thought the issue of racism would be the 
least important or difficult ethical problem with the Project. Everyone now says 
they are against racism, including, these days, every racist. We know where we 
come out on general principles. Difficult issues remain, but they are of a different 
nature from the discussions we just had over intellectual property. She urged 
that the Project consider intellectual property issues from a variety of 
perspectives, including the perspectives of the developing world and its 
advocates. 

She said the Project is likely to reinforce conventional understandings of 
race and ethnicity. For example, in current genetic screening programs, although 
geneticists and anthropologists emphasize that traditional race is arbitrary, 
screening programs use traditional ethnic and racial categories for the screening. 
This tends to make those categories seem more real. She could propose no 
solution, but it is one way in which the Project will have social implications. 

By contrast, she thinks that the specific results of the Project will neither 
reinforce nor undermine racism, but instead are likely to have very little effect on 
such attitudes. Dr. Mary-Claire King has said that the Project will undermine 
racism by showing how much alike we are; Dr. Paul said this is naive because 
the findings will not be clear-cut. The findings will be a set of statistics that will 
have to be interpreted to the general population. The discussion will be in terms 
of "more or less" -- is this is a substantial or insubstantial difference? It is like the 
nature/nurture controversy. Even if scientists put a number on the heritability of a 
trait, the number will not settle anything because some people will interpret the 
same result as large or small depending on their social interests. If the average 
human being is heterozygous at 10 percent of loci or if a population is 
polymorphic at one-third of loci, is that a lot or a little? It depends on the 
background assumptions brought to the question. She would not put too much 
emphasis on the consequences of the Project's results because, whatever they 
are, they will be controversial and will be invoked on behalf of every possible 
claim. 

She pointed out that it also is not easy to say what findings support the 
"progressive" side. In the classical balance controversy, which was a controversy 
about the extent of human diversity, H.J. Muller argued in the 1950s and 1960s 
that we are fundamentally alike. At the same time, Theodosius Dobzhansky 
argued that we were all very different, that genetic diversity was good for 
individuals and was good for populations, and therefore that we should expect to 



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find diversity maintained. For Muller it made sense to talk about a normal, wild 
type of a gene, and for Dobzhansky it was nonsense. 

Today we think that if the Project shows that people are all basically alike, 
that will be good and will undermine racism. But much of the bitter dispute 
between Muller and Dobzhansky flowed from the fact that they thought different 
social policies flowed from their views. In that dispute, Muller was the eugenicist 
and Dobzhansky was the anti-eugenicist. Dobzhansky wanted to show we were 
different in order to undermine Mullens eugenics policies. Muller's policies made 
sense if one thought there was genetic uniformity, because then one could 
conclude nature was striving for a best type. Dobzhansky wanted to say that 
nature loves diversity and people should not reduce diversity through eugenics. 
These policy implications are tremendously plastic, and the particular 
connections people make are highly contingent. As a result, Dr. Paul would not 
put much hope in the Project's undermining racism. Look at the former 
Yugoslavia; the Human Genome Diversity Project will probably not have much 
effect on that situation. 

Dr. William Schneider 

Dr. Schneider is chair of the Department of History at Indiana University- 
Purdue University at Indianapolis and has studied the history of research 
examining blood groups and populations. He began by saying that the Project's 
results will be misused, but it was not clear by whom. He noted that his analysis 
is based on his study of the history of similar efforts and not on a deep knowledge 
of current science. He did note, however, that the Project probably will not 
produce the results that are anticipated, because, historically, scientific projects 
rarely do produce the expected results. 

Dr. Schneider has studied the use of blood groups from 1900 to 1950 and, 
in particular, between the two world wars. He has looked at the work done by 
scientists from the discovery of blood groups and their inheritance according to 
Mendelian laws and primarily the discovery, during World War I, that blood 
groups were differently distributed in different ethnic groups. Hundreds of 
researchers published over 1200 articles in dozens of journals, analyzing tests of 
several hundred thousands of subjects in scores of countries and colonies 
around the world. As a result, this effort may have been larger than the proposed 
Human Genome Diversity Project. The most frequently asked question was 
whether blood groups could provide a different definition of race. Researchers 
were also interested in questions of links to disease, insanity, criminality, and so 
on. The working title of Dr. Schneider's project is "The First Genetic Marker"; the 
research he examines has both similarities to and differences from the Human 
Genome Diversity Project. 

The first similarity is that the blood group effort was based on a new scientific 
discovery, in its time probably as revolutionary as the genetics revolution. 
Second, blood grouping had immediate practical applications in blood 
transfusions. Third, the blood-group researchers wanted to explore differences 
between peoples. There had been earlier efforts, but, like the Project, the blood- 



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group researchers used new technology. The blood-group researchersers were 
also interested in the origins, movements, and mixings of populations. 

The blood-group research began with individual researchers finding samples 
from whatever groups they could, taking their samples, and publishing their 
results. Hospitals, soldiers, prisons, and mental institutions provided convenient 
sources for samples, as did the patients of doctors or missionaries stationed in 
remote parts of the world. The general model was that individual researchers did 
their work and published it in journals. Periodically, someone would publish 
compilations and analysis of that data. Some countries put forth systematic 
proposals similar to the Project. One of the most ambitious proposals was made 
in Germany in 1926, by the German Society of Blood Group Research. This 
Society, founded by a particularly "volkish" anthropologist named Otto Reche and 
a Navy doctor named Paul Stefan, divided the German world (including Austria) 
into 900 districts and called for the testing of 500 subjects in each district. It 
appealed for the cooperation of local doctors through publications in medical 
journals and in general-interest magazines. After about 1 2 studies, some based 
on school children, the Society asked the Prussian state welfare ministry to 
perform blood testing in all school districts. After the lengthy hearings, the 
council recommended only limited testing. The Society did not get what it wanted 
but it did get some legitimacy. It went on to create a journal to publish the results 
of the work of others. 

This interest was not limited to Germany. The Soviet Union created two 
research centers, one in Leningrad, which urged doctors to send samples to a 
central location for analysis under controlled conditions, and one in the Ukraine 
that followed the German model of asking doctors to do their testing on site. Two 
smaller countries, Holland and Denmark, persuaded their governments to support 
systematic studies of blood groups within their countries. Both of them used 
centralized analysis. Between 1919 and 1939, 75 countries and colonies were 
sampled with over 200,000 subjects. 

Was this used for racist purposes? Yes, in two ways. The first came from 
Hirzfeld's findings that a higher percentage of Type A blood was in northern and 
western Europe, with increasing proportions of Type B blood in central and 
southern Europe and moving into Asia. He devised something he called the 
biochemical index of race, which was simply a population's percentage of Type A 
blood divided by its percentage of Type B blood. Consciously or subconsciously, 
this meant that the highest numbers applied to northern and western Europe. It 
was fairly quickly recognized that the index did not work as a guide to 
conventional views of race, but studies through the late 1930s continued to use 
the Hirzfeld index to put the populations of the world into a hierarchy. 

In Germany, especially, the Aryan ideologists liked to show charts of the 
world based on the Hirzfeld index, interpreting the results as an invasion of 
Europe by Type B blood with Germany as a bulwark against this invasion. 

Similar kinds of studies were done in other countries as well. Gypsies, Jews, 
the Lapps, and Native Americans elicited particular interest. 



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Dr. Schneider asked whether this story has a moral. The research into blood 
groups and ethnicity did not represent a totally unmitigated disaster. The studies 
showed that the simplistic idea that a single number could define race was 
untenable. The blood groups ultimately provided a body of information that 
became a fundamental part for the whole field of human population genetics after 
World War II. The concept of race was different in 1949 than in 1919, at least in 
part because of this research. Thus, the research did make a difference, at least 
among scientists. This underscores the importance of access to information. It is 
a fundamental tenet of science that open access helps determine whether the 
truth will come out. You need to think long and hard before restricting any access 
to data. 

Dr. Eric Juengst 

Dr. Eric Juengst has a Ph.D. in philosophy and directs the NIH program on 
the Ethical, Legal, and Social Implications of the Human Genome Project. He 
began by saying that he is an optimist about the ability of the scientific and 
genetic community to anticipate and to manage the impact of its research. He 
sees as success stories for such active management both the recombinant-DNA 
debate in the 1970s and the procedures that came out of it and the discussion of 
gene therapy and the procedures that were developed for its assessment. He 
hopes that in the 1990s the Human Genome Project and its efforts to build in 
assessment will be a success story. He got involved in the Project because he 
thought we could anticipate the issues and prevent overly deterministic and 
reductionistic interpretations of personal genetic information and thus prevent 
"genetic discrimination." 

He believes the Diversity Project will take us to the next level of difficulty. 
The Diversity Project stands to inherit from the Human Genome Project the role 
of the lightning rod of genetics. The main social risk of the Human Genome 
Diversity Project is what he would call "demic" discrimination. This is not 
necessarily racism or racial discrimination, because "racial" categories look quite 
outdated, but discrimination against particular demes or subpopulations of the 
human community as a result of the misinterpretation or the misuse of the 
conclusions of studies done with the data collected by the Diversity Project. He 
sees three reasons to think the Project should anticipate such demic 
discrimination. 

First, unless it is very careful with its educational efforts, the Project is likely 
to be perceived by the public as an effort designed to establish a taxonomy of 
human types and categories. That will inevitably bolster contemporary notions of 
race and ethnicity. The statement from the first workshop report that the plan is 
to identify "the most representative descendants of ancestral human 
populations" worldwide and then preserve the genetic sequences suggests a 
typology. The counterargument is that the Project will find more similarity that 
difference but this is called the Human Genome Diversity Project, not the Human 
Kinship Project or the Human Family Project, because the scientifically 
interesting parts are the differences. 



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At the very least, a massive educational Project like the one planned for 
Europe is probably a prerequisite for the Project as a whole. That means the 
Project will necessarily have a high profile; there will be no chance to do this 
quietly. Vital issues are how the Project will be perceived and interpreted and 
whether it be perceived as a typology of human types that begins to look like a 
search for the "pure strains" of various types of humanity. 

Second, the findings the Project is expecting could be used to fuel existing 
human antagonisms. At the top of the list of the scientific questions are 
questions about relations to neighboring groups and questions of migrations -- 
when groups arrived in particular areas. But, he noted, lineage and land tenure 
are probably humanity's favorite excuses for making claims about social privilege. 
New scientific evidence bolstering the claims of one party or another could easily 
fuel existing fights. One can envision two scenarios. In one, the dominant group 
in a society is included in the Project, has its DNA hallmarked, and uses those 
hallmarks as inclusion criteria -- if you want to be part of the ruling group, you 
need to have the right DNA marking. The other side could be the flip side -- a 
dominant group uses DNA marking to identify groups for oppression. These 
groups would have to have access to appropriate DNA types or hallmarks to plug 
into a system of forensic DNA typing, but that will probably coming anyway, given 
police interest in this methodology. 

Third, one reason this Project is urgent is that many of the populations are 
vanishing. Why are they vanishing? Some are being assimilated into larger 
populations for no particularly nefarious reasons, but others are vanishing 
because they are at political or social or economic disadvantage and can no 
longer maintain the cohesion of the communities that once sustained them. That 
suggests that some of these demes already face political risks. Dr. Juengst likes 
the approach of starting with the least politically risky groups, in order to learn 
from experience what problems to anticipate and how to avoid them. 

What can we do to minimize these dangers? Dr. Juengst had two 
suggestions. First, the Project should be preceded by an educational campaign 
to define the Project to the public. It would be very dangerous to allow others to 
say what the Project is about; it would be much better for the Project to take an 
active role in presenting itself to the public. 

Second, he suggested that the Project should include a standing advisory 
group, akin to an IRB, to review requests for access to information. This group 
would ask researchers why they wanted the data or samples and what they 
intended to do with them. Such a group could serve to limit the misuse of the 
Project's data. 

Dr. Luca Cavalli-Sforza 

Dr. Luca Cavalli-Sforza is a geneticist at Stanford and a founding member of 
the Human Genome Diversity Committee. He began by defining racism as a 
belief in the biological superiority of some group. He noted that there is no 
biological basis for this belief, either in terms of genotype or in terms of 
phenotype. To the extent arguments are made for one group's superiority, they 



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are always based on phenotype and mainly on behavioral traits about which we 
have very little genetic data. 

Questions of the genetic basis of IQ became controversial about at the same 
time Dr. Cavalli-Sforza arrived in the United States in 1971. Arthur Jensen, 
encouraged by physicist William Shockley, argued that IQ had a substantial 
genetic basis and that the American black population had lower IQ's than the 
white population for genetic reasons. In fact, this argument was based on bad 
science in a variety of ways, and scientists, including himself, exposed its 
shortcomings. 

The traditional concept of race is not biologically meaningful. There is usually 
as much or more genetic diversity among the inhabitants of one isolated village 
as there is between population groups. If we want to understand something 
about human anthropology or history, we need to look at hundreds of traits 
because differences between groups are very small and otherwise comparisons 
are statistically inadequate. This DNA work will only confirm what we already 
know to be true about the meaninglessness of race. It is extremely likely in fact 
that this project will reinforce the current notion, obtained from thousands of 
studies of immunological and protein-electrophoretic variations, that there are no 
discontinuities among human groups that justify the concept of race. It should 
also be emphasized that when we speak of diversity we refer to diversity among 
individuals, but it would be silly to limit the study to individuals of a single, narrow 
group. We already know that when we do so we obtain results that are biased. 
Unfortunately, most existing data aware not ideal for evolutionary studies 
because they have been made with genetic variants detected in people of 
European origin. The study of diversity among individuals should be done on an 
appropriate sample taken from the whole world. By choosing it judiciously we 
can obtain information of enormous historical importance, which will be soon 
destroyed if we do not proceed before economic development cancels the 
residual differences among ethnic groups. 

He believes most people are convinced there is a true discontinuity among 
ethnic groups, thus justifying the idea of races, and that they derive this belief 
from the fact that we are all the time confronted by conspicuous differences in 
skin color and body and face shapes. These traits tend to be reasonably 
homogenous among individuals of one ethnic group, and different from those of 
another group. Such traits, however, are far from representing a random sample 
of genes. They most probably are due to an adaptation to different climatic 
conditions, made necessary by the evolutionary history of humans. The average 
genetic trait does not show the same homogeneity within groups and differences 
among groups as skin color and other external traits known to be influenced by 
climate. 

He agreed that an educational effort is a good idea. He noted that the 
Project will not add much to the forensic uses of DNA technology because the 
groups to be sampled are not generally of forensic importance in the countries 
that are pursuing forensic technology. 



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Discussion 

Prof. Greely opened the discussion by asking how can we minimize the 
misuse of the Project and whether the concerns are so great that the Project 
should not proceed. 

Dr. Paul said that she had little confidence in the ability of educational 
campaigns to improve public understanding. Dr. Siniscalco stressed the 
importance of the Project for "euphenics," improving the phenotype of humans 
through a better understanding of the interactions of genes and environments. 

Dr. Kenneth Weiss pointed out that racism is much older than science and is 
based in differentiating one group from another. Racists will always find data to 
misuse, whether or not it comes from the Human Genome Diversity Project. 

Dr. Bodmer asked what group would be appropriate to oversee the use of the 
Project's data. 

Dr. Mark Weiss noted that there is plenty of data in the published literature 
that could be used for racist views. If someone wanted to use the Project's cell 
lines to generate new data, he would need a fairly complicated lab. Dr. Weiss 
also noted that there are plenty of examples of racism in modern America, 
sometimes from surprising directions, and pointed to some aspects of the 
Afrocentric movement as an example. 

Dr. Feldman noted the distinction between misusing bad data, as Jensen did, 
and misusing techniques in manipulating good data. The markers that 
geneticists use today are racially biased because they are drawn from white 
populations, thereby making them, for many purposes, incomplete. He also 
noted that data can be abused by omitting some data, as in one study that 
purported to show a high degree of heritability on the basis of studies of 44 pairs 
of twins, while omitting data on another 1 1 1 twin pairs. 

Dr. Hollander stated that the Project does have an ethical obligation to seek 
to limit misuse. She noted that reactions to the Project vary in part with 
individuals' different levels of hope and fear. She would make a very different 
prediction from Dr. Cavalli-Sforza, but we cannot know in advance what the 
effects will be. How can we address problems when we can't know their full 
dimensions? 

Dr. Paul noted that Dr. Juengst had suggested the Genome Project as a 
model, but she argued that it is a flawed model. With the Genome Project, the 
scientific work goes forward and the Ethical, Legal, and Social Implications 
program goes forward, but the conclusions of the ethical, legal, and social 
implications program affect the science, if at all, in ways that are highly mediated 
and perhaps not very effective. If the Project is going to take these issues 
seriously, it needs to set up some kind of forum that is involved in making 
decisions on how to proceed on the technical side. If the ethical concerns are not 
integrated with the technical decision, they will not be effectively addressed. 



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Dr. Hollander noted that Dr. Juengst had earlier argued for involving the 
affected communities. This involvement needs to be addressed not only in the 
design of the project, but in some kind of continuing oversight, monitoring, and 
reconnaissance effort. If for no other reason, having community representatives 
involved will prepare the Project to have these conversations again and again, as 
it explains itself to the world. 

Dr. Paul said the Project needs to leave open the question of calling a halt in 
case the problems turn out to be worse than anticipated. The second question in 
section three of the agenda for this meeting was whether the concerns about 
such misuse are so great that the Project should not be undertaken. She said 
that the discussion had taken for granted that the answer to that is "no," but that 
she believes it should be an open question. Prof. Greely noted that he had put 
the question on the table and that there had not been any effort to "hide" that 
question; calling an open workshop at NIH is not consistent with trying to avoid 
the question. 

Dr. Eckstrand pointed out that NIH has a policy of openly sharing resources 
regardless of what those resources are. The example she knows best is 
GenBank, the database for all the DNA sequences that have ever been 
published. It is available to anyone who wants to tap into it. GenBank is 
maintained by the scientific community, and people have the right to use or 
misuse the data. By and large, the misuses have been honest scientific ones. 
She cannot imagine NIH saying it should have a resource of this nature and not 
make it available to anyone who wants to use it. 

Dr. Kenneth Weiss said first that he knows people from American minority 
groups who are offended that the Human Genome Project is using their tax 
dollars but is not including them. African-Americans know that a lot of medical 
genetics cannot be done for them because we don't know enough about their 
genotypes. If it were decided that it was not important to sample the rest of the 
world, it would be saying, in effect, that nothing out there is different or important. 
We know, he said, that this is not true. 

Second, before the second planning workshop, which he organized, he had 
expected the Project to produce a great deal of controversy among 
anthropologists, who as a group are very sensitive to these problems. Instead, 
there was almost universal enthusiasm for this. And for biomedical reasons, 
given the acceptance of the infinite-alleles model that most mutations are unique, 
there is no excuse for not sampling everyone. He said we know that mutations 
are going to be different in different peoples. Some of the populations the Project 
should sample represent tens of millions of people in the United States alone. 

Dr. Juengst said he thought for the Project to have this conversation in public, 
with the press in the room, was a great beginning. More generally, he noted that 
no one present had criticized or dismissed the reasons to do this Project. 
Instead, the discussion has centered on how to execute the Project without 
causing more trouble than necessary. 



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Dr. Cavalli-Sforza said he was glad that the NIH policy is to have everything 
open. That is how science should proceed. He then noted that data on some 
250 genes have already been collected by classical (non-molecular) techniques. 
That information is not as good as the data at the DNA level sought by the 
Project, but it has been collected from a great number of populations. These data 
have shown that genetic differences between races are small, and perceptible 
only by statistical investigations. There is no reason to think that analysis at the 
DNA level will change the picture; in fact, we already have enough information to 
be confident that it will not. What harm can come out of data of the new type? A 
trait like IQ is a product of perhaps 200 genes, which are likely to interact in 
complicated ways and, in addition to react to a poorly known set of external, non- 
genetic factors and events. It is difficult to believe that a satisfactory analysis of 
such complicated situations regarding behavioral traits will be possible in the near 
future, perhaps not even in time for the younger people in this audience to see. 

Dr. Murray then arrived and, after a break, spoke. 

Dr. Robert Murray 

Dr. Robert Murray is a physician and a faculty member in clinical genetics at 
Howard University. He has long worked with issues of genetic diversity and 
genetic screening in African-American populations. He began by noting that he 
had been involved in these kinds of issues for some time. Howard University has 
been collecting samples and information on genetic diversity among African- 
Americans. His experience has made him concerned about the possible misuse 
of genetic information concerning populations with respect to behavioral or social 
issues. Thus, for example, people might use information about a genetic 
propensity to low birth weight in one African population to argue that the problem 
with low-birth-weight African-American infants was "genetic" and should not be 
used to justify improving living conditions or medical care. 

Dr. Murray said he had just come from the AAAS meeting earlier in the week. 
At that meeting, the media were interested only in the question of crime and 
heredity, even though there is no data to support a true genetic relationship. He 
had been interviewed three times, not to discuss genetic screening, which he 
knows something about, or genetic engineering, for which there is some 
information, but about crime and heredity, where there is nothing to discuss. A 
person who misuses the Project's data will have a ready platform unless there is 
a quick response from someone the press can turn to for information. 

Concerns about the social uses of information on genetic diversity arose 
because of the pressure in the black community to do a better job of collecting 
bone marrow and kidneys for transplantation. Many people expressed the worry 
that the existence of different markers would be used to suggest that "these 
people" should be kept separate. 

Dr. Murray said the risk of harm comes from when studies are released and 
how they are reported. It is important that data be reported only when 
researchers have a substantial amount of information. For example, in the past 
few years, highly publicized studies have reported genetic linkages for manic- 



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depressive syndrome, alcoholism, and other traits. Those linkages were then 
disputed. Word of the initial studies is widely distributed, but the follow-up that 
the linkages may not exist gets much less publicity. As a result, people continue 
to believe, erroneously, that these linkages have been proven to exist. 

Our society talks about populations with different backgrounds and 
characterize certain life styles as "primitive" or "underdeveloped" when those 
populations live lives very different from ours. If significant genetic differences 
turn up in markers for these populations, some will attempt to attribute their 
cultural status to a genetic basis. Wilson's views of sociobiology are believed by 
many people who think much of our behavior is genetically controlled. 

Dr. Murray said he hoped that, in the design of the Project and whatever 
standards are set for the reporting of the data, significant thought will be given to 
providing responses or rebuttals to people who draw unjustified conclusions from 
the Project's data. 

Discussion 

Prof. Greely noted that Dr. Juengst had earlier suggested something like an 
IRB to see who should have access to data. He noted that Dr. Murray's concerns 
might be allayed by an entity that would have advance warning of what was being 
explored and perhaps even what results were to be published. This entity could 
constitute a "ready-response team" to try to put findings into perspective. 

Dr. Murray said that this had been tried with gene therapy. The human gene 
therapy subcommittee spent a lot of time drawing up guidelines, including some 
concerning dealing with the media. They were primarily concerned about early 
reports' giving false hope if, for example, someone gets evidence of gene transfer 
in one particular case. 

Dr. Siniscalco reminded the group that this Project is the best opportunity to 
collect this kind of data. Knowledge may be misused but we know that ignorance 
is at the basis of every misconception. The Project, he said, will give us a chance 
to understand not just history but the relationship between genetic makeup and 
environmental influences. In Sardinia, within the space of a few hundred miles, 
there were major ecological differences and human populations with substantial 
inbreeding. This has led to huge genetic differences based on the degree of 
exposure to malaria. The misconceptions of people like Dr. Jensen will draw 
forth responses from people like Dr. Cavalli-Sforza to correct them. We need to 
record these differences before human intermingling makes it too late. We must 
get the data; issues of the possible misuse of the information will be dealt with as 
it is interpreted. Otherwise, we will not be able to accumulate the knowledge that 
could benefit everyone. 

Dr. Porter noted that the discussion has brought out issues of how much 
should be centralized and decentralized. Dr. Juengst's proposed oversight body 
would be a centralized effort to ensure the highest standards of scientific review 
of the work that will be done on a decentralized basis. Centralization also will 
help in informing the press and in dealing with the political process. There will 



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necessarily be some disadvantages to becoming too centralized, including 
possible stifling of academic freedom or new uses for the data, but the question 
of centralization or decentralization is one useful way to think about these issues. 
What kind of oversight body would the Project want to construct to get the work 
going and to keep it going? 

Dr. Kenneth Weiss said that all that the Committee is proposing so far is to 
organize the collection of data, not to do any kind of analysis of that data, except 
to run a standard set of markers on all samples collected worldwide. The 
Committee has not proposed that the Project should be responsible for 
administering grant applications for analysis. What happens after sampling is a 
question the Committee has not considered, although it is a valid one. 

Dr. Murray said the problem is that collecting the samples will provide a 
source for abusive kinds of analysis. He had not thought there was any question 
about the Project's going forward. He thinks it should go forward -- on the whole, 
it will be beneficial rather than harmful. However, just one or two instances of 
misuse could destroy all the good the Project will do. The University of Maryland 
debacle undercuts all the good work geneticists have tried to do. He does not 
want that to happen with this Project. The discussions today are about trying to 
design the Project in a way to minimize the possibility of misuse of the data. The 
Project cannot divorce itself from responsibility for possible misuse, although it 
might want to. 

Dr. Kenneth Weiss replied that the Committee was very concerned that the 
data be open and not be seen as the private domain of two or three labs. Once it 
is open, it becomes like GenBank. GenBank is only statistical; CEPH (the Center 
for the Study of Polymorphisms in Paris) might be a better example because it 
provides physical samples and not just data. He asked whether anyone could 
get samples from CEPH? 

Dr. Cavalli-Sforza replied that after a request, CEPH writes to members of 
CEPH asking for information about the scientific validity of the planned research. 
CEPH makes an investment in sending DNA to people for free. Its data bank is 
accessible to all members, but there is a screening process for getting DNA. 
CEPH can turn people down if their proposed work is not sufficiently interesting 
for the linkage project. Dr. Feldman noted that CEPH is more restrictive than the 
Human Genome Diversity Committee had intended the Project to be. Dr. Cavalli- 
Sforza was concerned about whether access should be limited or whether, if NIH 
funds were used, it could legally be limited. Prof. Greely pointed out that there 
may not be a true dichotomy between limited and open access. One could have 
open access for researchers to cell lines, but require information about the 
planned studies and advance notice of the results. 

Dr. Evans noted that access involves both the cell lines and the data 
generated from that material, which will be in the data bank. The Project might 
want to have the data freely available, while demanding information about a study 
before giving access to samples. Someone noted that this would not require a 



28 



81 



screening committee, but perhaps just an organization that watched how the 
information was being used and what issues might be arising. 

Dr. Murray said the discussion of open access reminded him of the early 
days of sickle-cell testing, before there were any requirements for laboratory or 
professional certification. Many people were performing sickle-cell testing without 
any background, and they did lots of harm. He doesn't think the Project wants 
this material to be accessible to people without scientific background. If it does, 
one of his nightmares will come true. Someone with mischief on their mind will 
ask for the materials for the purpose of doing something harmful with them. 

Dr. Mark Weiss said he had just been looking at the catalog of cell lines from 
the National Institute of General Medical Science. That catalog, he noted, 
qualifies the meaning of "open." Cell cultures and DNA samples are distributed 
only to qualified professional persons who are associated with recognized 
research, medical, or educational institutions, so it will not be sent to absolutely 
anyone. Dr. Eckstrand agreed that a researcher could not just write in from her 
home address, particularly because that material is limited. If the material is 
unlimited, such as the DNA database, then NIH has made it open to anyone. 
She was not sure whether cell lines should be classified as limited or unlimited. 
Dr. Feldman asked whether NIH imposes any restrictions. If someone writes in 
and says they have money from a rigi.t-wing foundation and he wants a sample, 
would NIH provide it? Dr. Eckstrand replied that if he writes in from a recognized 
institution, the bank might check with its project officer and would probably be 
advised to send the cell lines. 

Dr. Giddings noted that the U.S. Department of Agriculture had had similar 
problems. He thinks the Project needs to be aware of the potential for misuse 
and to have contingency plans to deal with it. It should not restrict access, but it 
should be prepared to respond to abuses. 

Prof. Greely gave as an example: the Project learns a researcher is about to 
claim that, on the basis of data from the Human Genome Diversity Project, all 
Irishmen (his own ethnic background) were inherently prone to alcoholism. In 
that case, the Project could have a spokesman prepared to put that claim into 
perspective for the press. 

General Closing Discussion 

Prof. Greely noted that the meeting's time was nearly up. He invited people 
to discuss any other issues they thought were particularly important (while adding 
that he would be happy to hear comments on any of those issues later). 

Dr. Murray said that education about the goals and limits of the Project could 
help prevent a lot of problems. It was noted that there was fairly general 
agreement about the value of education. 

Dr. Siniscalco said that classifying populations is an old habit of people. We 
may now be able to classify people more scientifically, but that is not necessarily 
a bad thing. We have moved from eugenics to euphenics, where we can try to 



29 



82 



make the life of everyone equal regardless of what genes they are born with. To 
do that, we need to understand the relationship between genes and environment, 
which is what this Project is about. 

Prof. Greely and Dr. Feldman both thanked the participants sincerely for their 
useful discussion of these issues, and, at 4:00, the workshop concluded. 



30 



83 



APPENDIX A 



Human Genome Diversity Workshop on 

Ethical and Human Rights issues 

February 17, 1993 

This document contains a schedule for the workshop, a non-exclusive list of 
issues that may be discussed, and a listing of the workshop participants. 

Schedule 

Within each roundtable discussion, the participants are listed in the order in 
which they are currently expected to speak, although those orders are subject to 
change. Each participant should take, at most, 10 minutes for opening comments. 
Most of the time during each roundtable should be used for discussion of the issues 
among the participants and the audience. 

9:15 Opening -- Prof. Hank Greely, Stanford Law School (moderator) 

Summary of HGD-- Dr. Marcus Feldman, Stanford 

9:30 Roundtable Discussion of Issues Raised Issues Raised by the Possible 

Commercial Value of the Project's Samples, Data, or Findings 
Dr. Val Giddings, USDA 
Dr. Walter Reid, World Resources Institute 
Dr. Jason Clay, Cultural Survival Inc. 

10:50 Break 

1 1 :00 Roundtable Discussion of Issues Raised by the Sample Collection 

Process 

Dr. Ken Weiss, Pennsylvania State University 

Dr. Gary Ellis, NIH Office of Protection from Research Risks 

Dr. Rachelle Hollander, NSF 

Dr. Joan Porter, NIH Office of Protection from Research Risks 

12:30 Lunch 

1 :30 Roundtable Discussion of the Possible Misuse of Project Data or Results 

Dr. Diane Paul, University of Massachusetts at Boston 
Dr. William Schneider, Indiana University-Purdue University at 
Indianapolis 

Dr. Robert Murray, Howard University 
Dr. Eric Juengst, NIH 

3:00 Break 

3:10 General Discussion of Other Issues, Including Organization 

Participants and audience 

4:00 Scheduled Conclusion 



A-l 



84 



ISSUES 



The following pages contain a list of some of the issues that may be discussed 
at the workshop. This list, in somewhat earlier form, was circulated to the participants. 
The list is not intended to preclude discussion of other issues, although issues that do 
not relate to one of the three roundtables may be referred, at the moderator's 
discretion, to the afternoon's general discussion period. 

/. Issues Raised by the Possible Commercial Value of the Project's Samples, 
Data, or Findings 

This area includes a number of issues related to property, financial arrangements, and 
technology transfer. These issues are ethical and political. I believe we should deal 
with them first, because they have some implications for the second set of issues 

A. Payment Arrangements in the Event the Project Has Commercial Value 

1 . What is the potential for the commercial use of the project's data or results? 

2. Is it ethically permissible to pay, even in a contingent manner, for a human's 
DNA, or does that impermissibly "commodity" that person and demean his or 
her humanity? 

3. Will some governments demand a system of payment for any commercial value 
from the gene samples collected by their citizens? 

4. If so, how should the project respond? 

5. Should the project volunteer a uniform payment system for all countries, 
regardless of whether they request one? 

6. If the project were to agree to a kind of "royalty" arrangement, how should it be 
handled? 

a. Should the payment be based made on behalf of ail the populations 
sampled or just to those whose samples contributed to the commercial 
value? 

b. Should the payments be made to the governments of the relevant 
populations, or to the populations directly? 

c. If payments were to be made to populations directly, how should that be 
accomplished? 

B. Payment Arrangements and the Sampling Process 

1 . Should the payment arrangements reached, if any, or the absence of such 
arrangements, be part of the informed consent to individuals whose DNA is 
sampled? 

2. Should those arrangements be subject to renegotiation by each sampled 
population? 

3. Should the informed consent ask the sampled individuals expressly to release 
any property rights they may have in the samples or in the use of their DNA? 

4. Is it appropriate to provide any gifts or any payment to people who agree to 
participate? 

//. Issues Raised by the Sample Collection Process 



A-2 



85 



This area includes a number of issues revolving around how the samples are taken 
and how information obtained from the samples is used with respect to those people 
sampled. 

A. Who Should Be Sampled 

1 . Should the project ever sample children? 

2. If the project will sample children, what special protections should apply? 

3. How should adulthood be defined for these purposes -- by American standards, 
by those of the sampled population, or by both? 

4. Are there other classes of potential donors who deserve special consideration? 

B. Informed Consent 

1 . Should the project require a uniform manner of informed consent among all 
sampled populations? 

2. If variable methods of informed consent (written, oral, etc.) are permissible, 
considerations should be relevant in deciding the method to use with a 
particular population? 

3. Should the project ever accept the informed consent of one person as binding 
other persons (local leader and population, husbands and wives, parents and 
children, etc.)? 

4. Should the project ever permit someone other than the person to be sampled 
(a local leader, spouse, parent, etc.) to veto that person's participation? 

C. Privacy 

1 . What level of privacy should the project seek to ensure in the sampling process, 
with respect to the informed consent and the actual decision to donate or not? 

2. Should the samples, once taken and processed, continue to be identified with 
individual donors? 

D. Handling the Samples 

1 . Should the blood samples be screened for any disease organisms? 

2. If so, is the screening primarily to protect people who may come in contact with 
the samples in the future or to help the individuals who gave the samples? 

3. If any samples are to be screened for any disease organisms, who will decide 
what screening will be done and what considerations should that decision- 
maker apply? 

4. If a sample is screened and is found to be contaminated with a pathogen, 
what should be done with the sample? 

5. If a contaminated sample is found, should the person who donated the sample 
be told? Under all circumstances? Under some circumstances? Under no 
circumstances? 

6. Does the project have an obligation to provide medical assistance to individual 
donors who are found, through the project's work, to have medical conditions? 



A-3 



86 



///. Issues Raised by the Possible Misuse of Project Data or Results 

This area involves mainly the possibility that the project's existence, data, or 
findings will be used to claim that human populations are more different than the 
science supports and that these differences have social or political implications. The 
concern about such misuse stems from two reasonable fears. First, some people may 
try to use the project to support racist or nationalist claims of the "genetic superiority" of 
particular populations. Second, well-intentioned laymen may misconstrue some of the 
project's findings to similar ends. 

1 . Based in part on the history of cultural use of genetic information, how likely is 
such misuse of the project? 

2. Are the concerns about such misuse sufficiently great that the project should not 
be undertaken? 

3. If this research is not undertaken through the HGD project, will it be undertaken 
by others in any event? 

4. Should access to samples or data from the project be widely available, or 
should they be limited to researchers with appropriate academic credentials? 

5. Should access to samples or data from the project be limited on political 
grounds? 

6. Does the project have an ethical obligation to try to educate the public about the 
meaning of its results? If so, how should that obligation be fulfilled? 

IV. Other Issues 

This area is a catch-all for other ideas. We will discuss these are the end of the 
workshop to the extent we have time (and energy) left. This list currently contains only 
two areas of issues, but more are expected to surface during the day's discussion. 

A. Technology Transfer 

1 . How should the project respond to a request from a host country for technology 
transfer? 

2. Even without such a request, should the project feel an ethical obligation to 
attempt to transfer relevant technologies to the countries or the populations in 
which it samples? 

3. If the project should commit to technology transfer, how can such transfer best 
be accomplished? 

B. Organization 

1 . Should the project provide for some further consideration of ethical and human 
rights issues that it raises? 

2. How should that consideration be achieved ~ through an ethics advisory 
committee? through more workshops? through some other method? 



A-4 



87 



APPENDIX B 



Participants 

The following people are participating in the workshop discussions. The extremely short biographical 
material has not been cleared with all o» them; I regret any errors. 

Or. Jason Clay 

Cultural Survival, Inc., Boston, Massachusetts. Dr. Clay has a Ph.D. in anthropology. From 1980 to 1989. 

he was director of research for Cultural Survival, Inc., a nonprofit human rights organization working with 

indigenous peoples around the world. In 1989 he founded Cultural Survival Enterprises, which he 

directs. In that capacity he works to develop economic resources for indigenous peoples. 

Dr. Gary Ellis 

Office of Protection from Research Risks, National Institutes of Health. Dr. Ellis has a Ph.D. in Biological 

Sciences. He recently assumed the post of director of the NIH Office of Protection from Research Risks 

after several years as director of the Division of Health Promotion and Disease Prevention at the Institute 

of Medicine. 

Dr. Val Glddings 

Biotechnology, Biologies, and Environmental Protection Division, Animal and Plant Health Inspection 

Service, U.S. Department of Agriculture. Dr. Giddings has a Ph.D. in genetics. He is Chief of Science and 

Policy Coordination for the branch of the USDA that regulates the use of biotechnology products in the 

environment. Dr. Giddings was a member of the United States delegation that negotiated the Biodiversity 

Treaty, and he was particularly involved in the Treaty's technology transfer and royalty provisions. 

Dr. Marcus Feldman 

Stanford University, Department of Biological Sciences. Dr. Feldman has a Ph.D. in mathematical biology. 

A leading population geneticist, he is a member of the HGD Committee. 

Prof. Hank Greely(chalr) 

Stanford Law School. I am a law professor specializing in health policy. I have written on aspects of the 

Human Genome Project and on some aspects of bioethics. 

Dr. Rachelle Hollander 

National Science Foundation. Dr. Hollander has a Ph.D. in philosophy. She is director of the NSF Ethics 

and Values Studies Program. 

Dr. Eric Juengst 

National Center for Human Genome Research, National Institutes of Health. Dr. Juengst has a Ph.D. in 

philosophy. He is the principal ethicist with the NCHGR and directs its program on the ethical, legal, and 

social implications of the Human Genome project. 

Dr. Robert Murray 

Howard University, College of Medicine, Department of Genetics and Human Genetics (Chair). Dr. Murray 

is an M.D. He has written on genetic diversity among peoples of African origin and has long been 

interested in ethical issues concerning genetics. 

Dr. Diane Paul 

University of Massachusetts at Boston, Department of Political Science. Dr. Paul has a Ph.D. in political 

science and is the director of her university's Program in Science, Technology, and Values. She has 

written on the historical use of human diversity in the debates over eugenics and other social issues. 

Dr. Joan Porter 

Office of Protection from Research Risks, National Institutes of Health. Dr. Porter has a doctorate in public 

administration. She has served as Special Assistant to the Director in the Office of Protection from 

Research Risks for the past 1 1 years and has written on protection of human research subjects. 

Dr. Walter Reld 

Vice President for Program, World Resources Institute. Dr. Reid has a Ph.D. in zoology with a 

specialization in population and community ecology. His work has focused on world biodiversity. 

Dr. William Schneider 

Indiana University-Purdue University at Indianapolis, Department of History (Chair). Dr. Schneider has a 

Ph.D. in history. He has written on the historical uses of ethnic diversity in blood types in debates over 

eugenics and other social issues. 

Dr. Kenneth Weiss 

Pennsylvania State University, Department of Anthropology (chair). Dr. Weiss has a Ph.D. in anthropology 

and works in biological anthropology, epidemiology, and genetics, with a special interest in native 

American populations. Dr. Weiss is a member of the Human Genome Diversity committee. 



88 



Yale University 



Kenneth K Kidd.Ph.D 

Professor oj Genetics, 

Psychiatry, and Biology 

Department of Genetics 

School of Medicine 

333 Cedar Street 

PO. Box 3333 

New Haven. Connecticut 06510-6005 



Campus address: 
1-309 Sterling Hall of Medicine 
Telephone: 203 785-2654 
Fax: 203 785-6568 



Senator Daniel Akaka 
720 Hart Senate Office Building 
Washington, D.C. 20510-1103 
Attn: Shane Merz 

Dear Senator Akaka: 



May 5, 1993 



Thank you for the opportunity to submit written testimony for the hearing the Senate 
Committee on Governmental Affairs held on April 26 to examine the potential benefits of the 
Human Genome Diversity Project. I am a very strong supporter of that project; indeed, I 
am a member of the committee that has been working to organize and obtain funding for the 
project. As a committee member I have participated in preparing answers to the questions 
you directed to Prof. Hank T. Greely in a letter dated April 28, 1993. Today, however, I 
wish to make a personal statement. Rather than reiterate many of the points already made in 
the testimony of other supporters of the project, points with which I fully agree, I will use 
this opportunity to emphasize additional concerns. 

As a human geneticist I have strongly supported the Genome Project since its 
inception but always maintained that it had too narrow a focus. Genetic variation is a 
fundamental aspect of the genome of any organism but the priorities of the Genome Project 
do not include the systematic investigation of normal human variation— no research funds are 
allocated to the study of human variation while millions of dollars each year go to studies of 
the genomes of other organisms— mice, fruit flies, and round worms, for example. Those 
studies of other organisms are scientifically valuable, but a balance is needed. A genome is 
two dimensional. One dimension is the sequence, the length; the other dimension is normal 
variation in that sequence, the breadth. We need to study the length and breadth of the 
human genome to understand it. 

The collection of cell lines and supplemental DNA samples that the Human Genome 
Diversity (HGD) project proposes to establish is designed to complement the existing 
Genome Project by providing that missing second dimension. Some studies of those samples 
are to be part of the HGD project but the samples will also be a resource for many kinds of 
studies that are themselves beyond the primary focus of the project. Already the small 
resource of cell lines that exists in my laboratory has led to medically significant findings on 



89 



Senator Daniel Akaka 
May 5, 1993 
Page 2 



normal variation. For example, normal variation in receptor molecules of pharmacological 
importance has been shown. This variation does not cause a disease, but can determine 
individual response to medications and may make it possible to predict drug effectiveness 
based on a simple genetic test. Some ethnic groups, such as Japanese, have variant forms of 
these molecules not seen in Europeans. In total we found 9 forms in Europeans and an 
additional 14 forms in the other populations we sampled. This is a clear example of how 
basic research findings in normal genetic variation can have significant clinical applications. 
Scientifically valuable studies, impossible to envision today, will be developed using the 
knowledge gained from the Genome Project and the resources available from the Human 
Genome Diversity Project. 

The National Institute for General Medical Sciences (NIGMS) has in place a 
mechanism which could be expanded to deal with the cell repository aspects of the HGD 
project. There exists a very small collection of cell lines on diverse human populations in 
the Coriell Institute for Medical Research, Camden, New Jersey, sponsored by NIGMS. 
This collection consists primarily of a few cell lines from a few of the populations Prof. 
Cavalli-Sforza and I have been able to assemble over the past several years. Dr. Mulivor, 
Director of the Human Genetic Mutant Cell Repository, has informed me that this small 
collection is already one of the ten most important in the Repository in terms of the number 
of cell lines requested by investigators. 

A final consideration that has not yet been emphasized is that of training the next 
generation of scientists and physicians. Understanding variation requires knowledge, skills 
and perspectives that are different from those required for mapping and sequencing the 
genome. The necessary training and experience are best achieved through participation in 
research projects on normal variation. Without opportunity for the study of normal 
variation, the perception of young scientists will become one dimensional; variation will 
appear abnormal rather than normal. If we do not know the range of normal, how can we 
recognize the abnormal? 

Thank you for allowing me this opportunity to express my concerns. If I can be of 
any assistance in your Committee's deliberations, please do not hesitate to call upon me. 

Sincerely, 




Kenneth K. Kidd, Ph.D. 
Professor of Genetics, 
Psychiatry, and Biology 



KKK:rjm 



90 



Forum 

Human Genome Diversity Initiative 



JUDITH R. KIDD.' KENNETH K. KIDD, 2 AND KENNETH M. WEISS 3 



The international Human Genome Project (HGP) is an effort to map and 
then sequence the human genome, that is, to determine the DNA se- 
quence of all 3 billion nucleotide base pairs in the human DNA com- 
plement. This effort involves many agencies and countries and aims to 
identify, locate on their respective chromosomes, and sequence all func- 
tional genes, regulatory regions, and other DNA segments. Foremost 
among the many anticipated benefits of the project is that the data gen- 
erated will lead to a better understanding of the function and expression 
of human genes. Unfortunately, this huge undertaking does not include 
any systematic consideration of variation in sequence; that is, the HGP 
does not address that aspect of the genome that is of driving interest in 
anthropology: human variation. It is the variation of the DNA sequence 
among individuals, both within and between populations, that illumi- 
nates the unique history of each population. That historical record cannot 
be inferred from a standardized genome sequence or from a gene map 
derived from a composite individual. In this forum we review some of 
the uses of studies of variation and then describe the general structure 
of a new initiative to organize an international project to address DNA 
variation in the human species. 

The genome is not a simple homogeneous entity; it is composed of 
different elements, each able to yield information on aspects of our his- 
tory and evolution. Molecular genetic tools allow us to learn about the 
different elements and hence about our past. Although all regions of the 
genome are composed of nucleotides, the functional content of these se- 
quences varies. Each component reflects particular aspects of human 
evolution, each has a unique evolutionary tempo, and each affects and 
has been affected by our evolutionary history in ways different from the 
others. Detailed analyses of variation in all the components of the human 
genome will provide essential information to advance many fields of study, 
including functional studies, forensics, microevolution, and medical 
applications. 



'Departments of Anthropology and Genetics, Yale University, New Haven, CT 06510. 
: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510. 
'Department of Anthropology, Pennsylvania State University, University Park. PA 16802. 

Human Biology, February 1993, v. 65, no. 1, pp. 1-6. 

Copyright © 1993 Wayne State University Press. Detroit, Michigan 48202 



91 



2 / KIDD ET AL. 

Functional Studies. Classical issues of interest that have generally 
resisted definitive analysis include adaptation and the relationship be- 
tween genetic variation and phenotypic variation. New methods promise 
to revolutionize the study of these topics. Two problems confront us 
when we attempt to study phenotypic adaptation and control. The first 
is identification of the genes responsible for the phenotypic variation in 
question. In some cases animal studies and biochemical studies can iden- 
tify the relevant loci. Often, positional cloning based on family data and 
linkage studies is required to identify the specific locus responsible for 
adaptive variation. The second problem is that mutations continually arise 
in all loci and most new mutations are unique at the DNA level. This 
means that specific adaptations will often be local, and the evolutionary 
history of each area will often involve different mutations, even in the 
same genes. Reconstruction of human adaptive evolution will require 
study of genetic diversity in functional genes in different populations. 

Forensic Studies. There is a great deal of interest and controversy 
these days over the use of DNA data for forensic purposes, another of 
the traditional areas of interest to anthropologists. The method of DNA 
profiling relies on the fact that some short nucleotide sequences may be 
adjacently repeated a highly variable number of times. These repetitive 
regions are also called variable number of tandem repeats (VNTRs) or 
hypervariable regions (including both mini- and microsatellite DNA). 
Typically, a type of repeat sequence found in any given chromosomal 
region will be there in all persons (sometimes in other primates); how- 
ever, in such regions mutation may change the copy number so rapidly 
that even close relatives may not share the exact same copy numbers or 
DNA profile for both chromosomes at several such loci. 

One of the major forensic issues being debated is the degree to 
which the DNA polymorphisms being used for forensic identification can 
be interpreted when questions of small isolated populations are relevant 
to the specific case. The data collected so far show that for most loci 
the alleles have different frequency distributions in different ethnically 
defined samples. Those differences, however, are often small, especially 
for closely related populations. Even where the differences in allele fre- 
quencies are large, the number of alleles is usually still large in all pop- 
ulations. This suggests the generalization that any multilocus DNA phe- 
notype based on these VNTR loci is a rare one on a global basis. Exactly 
how rare can be determined only in the context of a specific population. 
Currently, good estimates are possible for populations of mixed Euro- 
pean ancestry, but those estimates do not generalize to other specific 
ethnic groups without either data specifically on the ethnic group or an 
assumption about the similarity of the ethnic group to those already studied. 



92 

Forum on Human Genetic Diversity / 3 



Microevolutionary Studies. To date, much discussion has centered 
on that aspect of genetic research that concerns the reconstruction of 
population relationships from a phylogenetic point of view. Most valu- 
able for this are selectively neutral sequences, that is, sequences that are 
likely to evolve in a more regular way as a result of genetic drift because 
they are not affected by natural selection. Phylogenetic relationships among 
populations are certainly one of the core problems in anthropology. 

The hundred or so single-copy nuclear DNA polymorphisms that 
have been studied on a global scale (albeit in a most preliminary way) 
show that almost all alleles exist in almost all populations. A corollary 
is that most polymorphisms examined are polymorphic throughout the 
species. Although balancing selection might be invoked for a few loci, 
to invoke it for many loci is not reasonable. Therefore we must conclude 
that diversification of modern H. sapiens is recent or that it has involved 
relatively large effective populations at all stages or both. Polymor- 
phisms found in all human populations are informative of our deeper 
history. Even when the individual polymorphisms differ only in fre- 
quency from population to population, the combinations of polymor- 
phisms that are molecularly close — haplotypes — can be characteristic of 
individual populations, thus reflecting the unique history of populations 
(e.g., migration, genetic drift), their relationships to one another (phy- 
logenetic relationships), and selection at nearby loci. Thus DNA poly- 
morphisms are useful for reconstructing both long- and medium-term 
human prehistory. 

Medical Applications. Clinical applications and medical anthropol- 
ogy are intertwined with population studies. The diagnosis of genetic 
disease, indeed even treatment, soon will depend on the identification 
of specific mutations at loci whose function relates to a given disease. 
Currently, genetic counseling, screening, and attempts at gene therapy 
are heavily concentrated in European-derived populations, with some ex- 
ceptions for Jewish populations (e.g., Tay-Sachs disease) and popula- 
tions affected with globin gene mutations such as sickle-cell hemoglobin. 
But for many diseases it has already become clear that the pathogenic 
mutations differ among populations. The mutations that cause phenyl- 
ketonuria in Asia are different from those in Europe, and the same pic- 
ture is emerging for every problem that is studied in genetic detail (in- 
cluding the abnormal hemoglobins). We know little about such variation 
in pathogenic mutations. Likewise, it would be difficult to screen pop- 
ulations in India or Mongolia, for example, for cystic fibrosis, given that 
most of the currently known mutations are identified in Europeans. 

This situation for rare diseases caused by single-gene defects con- 
trasts with the picture for common normal polymorphisms. The situation 
for more common but also more complex genetic diseases, such as di- 



93 

4 / KIDD ET AL 



abetes or neuropsychiatric disorders, is less clear. Indeed, we do not 
even know which loci (or how many) control such diseases, but it is 
possible that mutations at different loci will be important in different 
populations. For example, susceptibility to diabetes may have a strong 
genetic component in Amerindians, but to understand this we must find 
the locus (loci). This requires family studies and polymorphic genetic 
markers that can be used to find linkage between marker variants at some 
genome region and the occurrence of disease in families. The highly 
polymorphic repetitive elements may be the most powerful markers for 
this purpose. 



The Human Genome Diversity Initiative 

All the studies outlined here depend on the analysis and under- 
standing of genetic variation within our own species. A complete single 
composite sequence will provide little by way of answers to any of the 
research questions. To address the need for information on human bio- 
diversity, the Human Genome Organization (HUGO, an international 
scientific society) has established an ad hoc committee to formulate plans 
for and then organize a project on human genome diversity (HGD). That 
ad hoc committee has received funding for a series of international work- 
shops from a consortium of agencies, including the National Institutes 
of Health, the National Science Foundation, and the Department of En- 
ergy (in the United States), and additional support is being sought from 
agencies in Europe. These workshops have begun to formulate specific 
plans for how the HGD Project should be organized. Initially, the prob- 
lem is to rationalize collection of genetic resources so that data relevant 
to a wide variety of research questions can utilize common resources. 
By the time this forum appears in print, the written documents produced 
by the first of the workshops should be in circulation within the anthro- 
pology and human genetics communities for comment and criticism. Some 
of the issues and goals are already clear. 

The HGD Project aims to collect the biological resources that would 
facilitate, even be sufficient for, all the types of studies noted earlier. A 
worldwide selection of human populations needs to be chosen in a way 
that adequately represents our species and its history. The intention is 
that knowledgeable local investigators will help to identify the popula- 
tions to be sampled. Then, to ensure permanent samples that can be a 
resource for many studies, cell lines will be established from individuals 
in these populations. DNA or the growing cells themselves will then be 
available to the world research community at no profit or perhaps even 
at a subsidized cost. Investigators wishing to study questions such as 
those mentioned here will have access to the appropriate material in the 



BOSTON PUBLIC LIBRARY 

94 3 9999 05982 877 

Forum on Human Genetic Diversity / 5 



cell-line "bank." Cultural characterization of the populations studied is 
of recognized importance, but extensive data collection is beyond the 
scope of the Human Genome Diversity Project. The genetic research will 
be far more valuable if cultural anthropologists are able to mount re- 
sources and study the same populations. 

Exactly how the global HGD collection should be structured is a 
difficult and challenging problem that has at least three major aspects. 
First, there are the population genetics and statistical questions of how 
to sample: How many people should be sampled from how many local 
groups or geographic areas worldwide to provide an optimum resource 
for use now and in the future? Because many of these populations are 
rapidly losing their genetic distinctiveness through exogamy, it is im- 
portant that the structure of the sample be appropriate; we cannot go back 
in 50 years to correct errors of sampling made now. Second, there are 
the anthropological questions of whom to sample. Should small endan- 
gered populations (i.e., those whose genetic identity or even survival is 
threatened) be sampled preferentially to large major populations repre- 
senting predominant cultures? Which populations will provide the most 
information on the greatest number of questions? Third, there are many 
difficult issues of how to fund, maintain, and distribute such a resource 
and the data pertaining to it. Also, such a project should help the sampled 
populations, or at the least do them no harm. Useful technology transfer 
should also be an aim. How to address these three aspects is a difficult 
question. 

The existence of a properly designed HGD collection can be ex- 
citing and of widespread and long-term benefit to anthropologists and all 
scholars interested in human evolution, history, and prehistory. The HGD 
ad hoc committee has organized three workshops, one to look at each 
set of problems. In addition to those attending the workshops, many 
other interested investigators have already contributed ideas concerning 
each problem. These workshops are preparing working drafts of how the 
HGD Project will be organized. These working drafts are being circu- 
lated broadly and summaries are being published. The final documents, 
incorporating the responses to the workshop drafts, will provide the 
framework for researchers around the world to apply to funding agencies 
and governments for financial support to collect and maintain the sam- 
ples. This framework should facilitate allocation and availability of funds 
for this type of work, but we anticipate that actual funding will still be 
primarily through the awarding of research grants to individual research- 
ers on a competitive basis. 

The HGD Project can make fundamental contributions to applied 
and basic knowledge about human diversity. It will provide an impor- 
tant — many of us would say vital — corollary to the mapping of the hu- 
man genome and the development of a largely European-based sequence 



95 

6 / KIDD ET AL. 



of the genome. Those efforts are of basic importance to anthropologists 
and geneticists, but we all stand to benefit in a special way from the 
proposed attempt to represent the genetic diversity of our species as a 
whole. 



Received 9 June 1992; revision received 28 June 1992. 

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ISBN 0-16-043334-7 



9 780160"A33344 



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